Substituted benzimidazole-type piperidine compounds and uses thereof

ABSTRACT

The disclosure relates to Substituted Benzimidazole-Type Piperidine Compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts or solvates thereof, e.g., a pharmaceutically acceptable salt or solvate, wherein R 1 , R 2 , R 3 , Q a , W, U, A, B, Z, a, and the dashed lines are as defined herein, compositions comprising an effective amount of a Substituted Benzimidazole-Type Piperidine Compound, and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of a Substituted Benzimidazole-Type Piperidine Compound.

1. FIELD

The disclosure relates to Substituted Benzimidazole-Type PiperidineCompounds, compositions comprising an effective amount of a SubstitutedBenzimidazole-Type Piperidine Compound and methods to treat or prevent acondition, such as pain, comprising administering to an animal in needthereof an effective amount of a Substituted Benzimidazole-TypePiperidine Compound.

2. BACKGROUND

Chronic pain is a major contributor to disability and is the cause ofmuch suffering. The successful treatment of severe and chronic pain is aprimary goal of the physician, with opioid analgesics being preferreddrugs for doing so.

Three major classes of opioid receptors in the central nervous system(CNS) have long been known, with each class having subtype receptors.These receptor classes are known as μ, κ and δ. As opiates have a highaffinity for these receptors while not being endogenous to the body,research followed in order to identify and isolate the endogenousligands to these receptors. These ligands were identified as endorphins,dynorphins and enkephalins, respectively.

Experimentation eventually led to the identification of an opioidreceptor-like (ORL-1) receptor with a high degree of homology to theknown receptor classes. The ORL-1 receptor was classified as an opioidreceptor based only on structural grounds, as the receptor did notexhibit pharmacological homology. It was initially demonstrated thatnon-selective ligands having a high affinity for μ, κ and δ receptorshad low affinity for the ORL-1 receptor. This characteristic, along withthe fact that an endogenous ligand had not yet been discovered, led tothe term “orphan receptor.” See, e.g., Henderson et al., “The orphanopioid receptor and its endogenous ligand—nociceptin/orphanin FQ,”Trends Pharmacol. Sci. 18(8):293-300 (1997).

Subsequent research led to the isolation and structure of the endogenousligand of the ORL-1 receptor (i.e., nociceptin; also known as orphaninFQ (OFQ)). This ligand is a seventeen amino acid peptide structurallysimilar to members of the opioid peptide family.

The discovery of the ORL-1 receptor presents an opportunity in drugdiscovery for novel compounds that can be administered for painmanagement or other syndromes modulated by this receptor.

U.S. Pat. Nos. 6,872,733, 7,456,198, 7,495,109, and 7,678,809 disclosebenzoimidazolones or derivatives thereof as compounds having affinityfor the ORL-1 receptor.

U.S. Pat. No. 6,867,222 and U.S. Pat. App. Pub. No. 2008/0214827disclose cyanoimino-benzoimidazoles or derivatives thereof, and methodsfor making the same, as compounds for modulating the pharmacodynamicresponse from the ORL-1 receptor.

U.S. Pat. No. 7,939,670 discloses benzooxazolones or derivatives thereofas compounds for modulating the pharmacodynamic response from the ORL-1receptor.

U.S. Pat. App. No. 2010/0144591 describes benzoimidazole derivatives andmethods of using the same to treat or prevent pain.

U.S. Pat. No. 7,105,505 discloses benzoimidazole derivatives useful ashistamine H₃ antagonists.

U.S. Pat. Nos. 6,172,067, 6,340,681, and 6,861,425 disclose certainpiperidyl benzoimidazole compounds as ORL-1 receptor agonists.

U.S. Pat. App. Nos. 2003/0119869 and 2010/001007 describe certainbenzoimidazole compounds or piperidine derivatives, respectively, aschemokine receptor CCR5 modulators.

U.S. Pat. App. No. 2008/0287479 describes certain benzimidazol-2-onecompounds useful in the inhibition or modulation of serene palmitoyltransferase.

International PCT Publication No. WO 2004/069828 describes certainpiperidine compounds as therapeutic agents for schizophrenia.

International PCT Publication Nos. WO 99/46260, WO 99/50254, WO01/90102, WO 2005/028451, WO 2003/062234, and U.S. Pat. App. No.2005/0256000, respectively, describe quinoxalines or derivatives thereofas (i) inhibitors of protein kinase C, (ii) serine protease inhibitors,(iii) herbicides, (iv) M2 acetylcholine receptor agonists, (v)medicaments for diseases involving poly(ADP-ribose) polymerase, and (vi)safeners for plants.

Hayashi et al. (“Discovery of1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole:Integrated Drug-Design and Structure-Activity Relationships for OrallyPotent, Metabolically Stable and Potential-Risk Reduced NovelNon-Peptide Nociceptin/Orphanin FQ Receptor Agonist as AntianxietyDrug,” Chem. Biol. Drug Des. 74:369-381 (2009) and “Novel Non-PeptideNociceptin/Orphanin FQ Receptor Agonist,1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole:Design, Synthesis, and Structure-Activity Relationship of Oral ReceptorOccupancy in the Brain for Orally Potent Antianxiety Drug,” J. Med.Chem. 52:610-625 (2009)) disclose substituted1-(1-(1-methylcyclooctyl)piperidin-4-yl)-2-(piperidin-3-yl)-1H-benzo[d]imidazolessaid to be in vitro non-peptide full ORL-1 receptor agonists and oralanxiolytics in mice.

Hayashi et al., “Discovery of{1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol,systemically potent novel non-peptide agonist of nociceptin/orphanin FQreceptor as analgesic for the treatment of neuropathic pain: Design,synthesis, and structure-activity relationships,” Bioorg. Med. Chem.18:7675-7699 (2010), disclose substituted1-(1-cyclooctylpiperidin-4-yl)-2-(piperazin-1-yl)-1H-benzo[d]imidazolessaid to be non-peptide ORL-1 receptor agonists and provide an inhibitoryeffect against mechanical allodynia in rats.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY

In one aspect of the disclosure, new compounds that exhibit affinity forthe ORL-1 receptor are described.

In some embodiments, such new compounds exhibit agonist activity orpartial agonist activity at the ORL-1 receptor. In other embodiments,such new compounds exhibit agonist activity at the ORL-1 receptor. Inother embodiments, such new compounds exhibit partial agonist activityat the ORL-1 receptor. In yet other embodiments, such new compoundsexhibit antagonist activity at the ORL-1 receptor.

In another embodiment of the disclosure, such new compounds exhibitaffinity for the ORL-1 receptor, and also for one or more of the μ, κ orδ receptors. In some embodiments, a new compound of the disclosureexhibits affinity for both the ORL-1 receptor and the μ receptor. Inother embodiments, a new compound of the disclosure acts as an ORL-1receptor agonist or partial agonist and as aμ receptor agonist orpartial agonist. In other embodiments, a new compound of the disclosureacts as an ORL-1 receptor agonist and as a μ receptor agonist or partialagonist. In other embodiments, a new compound of the disclosure acts asan ORL-1 receptor partial agonist and as aμ receptor agonist or partialagonist. In other embodiments, a new compound of the disclosure acts asan ORL-1 receptor agonist or partial agonist and as a μ receptoragonist. In other embodiments, a new compound of the disclosure acts asan ORL-1 receptor agonist or partial agonist and as a μ receptor partialagonist. In other embodiments, a new compound of the disclosure acts asan ORL-1 receptor agonist and as a μ receptor agonist. In otherembodiments, a new compound of the disclosure acts as an ORL-1 receptoragonist and as a μ receptor partial agonist. In other embodiments, a newcompound of the disclosure acts as an ORL-1 receptor partial agonist andas aμ receptor agonist. In other embodiments, a new compound of thedisclosure acts as an ORL-1 receptor partial agonist and as a μ receptorpartial agonist. In other embodiments, a new compound of the disclosureacts as an ORL-1 receptor agonist or partial agonist and as a μ receptorantagonist. In other embodiments, a new compound of the disclosure actsas an ORL-1 receptor agonist and as aμ receptor antagonist. In otherembodiments, a new compound of the disclosure acts as an ORL-1 receptorpartial agonist and as aμ receptor antagonist. In other embodiments, anew compound of the disclosure acts as an ORL-1 receptor antagonist andas a μ receptor agonist or partial agonist. In other embodiments, a newcompound of the disclosure acts as an ORL-1 receptor antagonist and as aμ receptor agonist. In other embodiments, a new compound of thedisclosure acts as an ORL-1 receptor antagonist and as a μ receptorpartial agonist.

Certain new compounds of the disclosure can be used to treat an animalsuffering from chronic or acute pain.

In another embodiment of the disclosure, methods for treating chronic oracute pain in an animal by administering one or more SubstitutedBenzimidazole-Type Piperidine Compounds to an animal in need of suchtreatment are described. In certain embodiments, such new SubstitutedBenzimidazole-Type Piperidine Compounds effectively treat chronic oracute pain in the animal, while producing fewer or reduced side effectscompared to previously available compounds.

Compounds of formula (I) are herein disclosed:

or a pharmaceutically acceptable salt or solvate thereof where:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and        -   (c)-phenyl, -naphthalenyl, and -(5- or            6-membered)heteroaryl, each of which is unsubstituted or            substituted with 1, 2, or 3 independently selected R⁷            groups;

each dashed line denotes the presence or absence of a bond (i.e., when adashed line is present there is a double bond at that position and whena dashed line is absent there is only a single bond at that position),provided that:

-   -   (a) one dashed line must denote the presence of a bond (i.e.,        there is a double bond at one position);    -   (b) when one dashed line denotes the presence of a bond (i.e.,        there is a double bond at that position) then the other dashed        line denotes the absence of a bond (i.e., there is only a single        bond at that other position);    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present (i.e., there is a double bond at that position), then R³        is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent (i.e., there is only a single bond at that position),        then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂;

is a single bond, a double bond, ═CH—, —CH₂—, ═N—, —NH—, —O—,═CH—(C₁-C₃)alkylene-, —CH₂—(C₁-C₃)alkylene-, ═N—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,—CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-,—O—(C₂-C₃)alkenylene-, ═CH—(C₁-C₃)alkylene-N(R¹¹)—,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, ═N—(C₁-C₃)alkylene-N(R¹¹)—,—NH—(C₁-C₃)alkylene-N(R¹¹)—, —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—,—CH═N—, —CH₂—N(R¹¹)—, ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or—CH₂—O—(C₁-C₃)alkylene-;

U is:

-   -   (a) —R¹⁵; or    -   (b)

-   -    wherein when        is a single bond or a double bond the Q_(x) ring is a -(4-, 5-,        6-, or 7-membered)heterocycle containing one or two ring        heteroatoms selected from N,N(R⁴), O, and S provided that at        least one ring heteroatom is N or N(R⁴) and wherein either U¹ is        N and U² is a bond or U¹ is C or CH and U² is N or N(R⁴),        provided that;    -   (1) when        is a double bond and the Q_(x) ring is present, U¹ is C; and    -   (2) when        is ═CH—, —CH₂—, ═CH—(C₁-C₃)alkylene-, or —CH₂—(C₁-C₃)alkylene-        and the Q_(x) ring is present, the Q_(x) ring is a        (6-membered)heterocycle selected from:

-   -   (3) when        is ═N—, —NH—, —O—, ═N—(C₁-C₃)alkylene-, —NH—(C₁-C₃)alkylene-,        —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,        —CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-,        —NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,        ═CH—(C₁-C₃)alkylene-N(R¹¹)—, —CH₂—(C₁-C₃)alkylene-N(R¹¹)—,        ═N—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,        —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—,        ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or        —CH₂—O—(C₁-C₃)alkylene-, then the Q_(x) ring is absent;

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,        —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, or —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³;        and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b)—R¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, and 2;

when s is 1, R¹⁰ is —F, —CH₃, —CH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, the R¹⁰ groups together aregem-dimethyl, gem-difluoro, ═O, or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

R¹¹ is —H, —CN, or —C(═O)N(R⁶)₂ or R¹¹ is —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, or —N(R⁶)₂

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

R¹⁵, when present, is selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₄)alkyl and —O—(C₁-C₄)alkyl, each of which is        unsubstituted or substituted with 1, 2, 3, or 4 independently        selected R⁸ groups;    -   (c) provided that when        is a single bond, a double bond, or —O—, R¹⁵ is not —H;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

Compounds of formula (IA) are herein disclosed:

or a pharmaceutically acceptable salt or solvate thereof where:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected R⁷ groups;

each dashed line denotes the presence or absence of a bond (i.e., when adashed line is present there is a double bond at that position and whena dashed line is absent there is only a single bond at that position),provided that:

-   -   (a) one dashed line must denote the presence of a bond (i.e.,        there is a double bond at that position);    -   (b) when one dashed line denotes the presence of a bond (i.e.,        there is a double bond at that position) then the other dashed        line denotes the absence of a bond (i.e., there is only a single        bond at that other position);    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present (i.e., there is a double bond at that position), then R³        is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent (i.e., there is only a single bond at that position),        then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂;

t is an integer selected from 0, 1, 2, and 3;

when t is 0, the Q_(x) ring is a -(4-, 5-, 6-, or 7-membered)heterocyclecontaining one or two ring heteroatoms selected from N,N(R⁴), O, and Sprovided that at least one ring heteroatom is N or N(R⁴) and providedthat when the dashed line connecting the Q_(x) ring to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring is present(i.e., there is a double bond at that position), U¹ is C or CH, and

when t is 1, 2, or 3 the Q_(x) ring is a (6-membered)heterocycleselected from:

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X, —(CH₂)_(d)—        C(═Y)N(R⁹)YCH₂CH₂X, or —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³; and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b-R) ¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, and 2;

when s is 1, R¹⁰ is —F, —CH₃, —CH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, the R¹⁰ groups together aregem-dimethyl, gem-difluoro, ═O, or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any -(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any -(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

Compounds of formula (I*) are herein disclosed:

or a pharmaceutically acceptable salt or solvate thereof wherein:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected P7 groups;

each dashed line denotes the presence or absence of a bond, providedthat:

-   -   (a) one dashed line must denote the presence of a bond;    -   (b) when one dashed line denotes the presence of a bond then the        other dashed line denotes the absence of a bond;    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present, then R³ is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent, then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂;

is a single bond, a double bond, ═CH—, —CH₂—, ═N—, —NH—, —O—,═CH—(C₁-C₃)alkylene-, —CH₂—(C₁-C₃)alkylene-, ═N—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,—CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-,—O—(C₂-C₃)alkenylene-, ═CH—(C₁-C₃)alkylene-N(R¹¹)—,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, ═N—(C₁-C₃)alkylene-N(R¹¹)—,—NH—(C₁-C₃)alkylene-N(R¹¹)—, —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—,—CH═N—, —CH₂—N(R¹¹)—, ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or—CH₂—O—(C₁-C₃)alkylene-;

U is:

-   -   (a) —R¹⁵; or    -   (b)

-   -    wherein when        is a single bond or a double bond the Q_(x) ring is a -(3-, 4-,        5-, 6-, or 7-membered)heterocycle containing 1, 2, 3, or 4 ring        heteroatoms independently selected from N,N(R⁴), O, and S,        wherein said heterocycle is unsubstituted or substituted with        (R¹⁰)_(s), provided that at least one ring heteroatom is N or        N(R⁴) and wherein either U¹ is N and U² is a bond or U¹ is C or        CH and U² is N or N(R⁴), provided that;    -   (1) when        is a double bond and the Q_(x) ring is present, U¹ is C; and    -   (2) when        is ═CH—, —CH₂—, ═CH—(C₁-C₃)alkylene-, or —CH₂—(C₁-C₃)alkylene-        and the Q_(x) ring is present, the Q_(x) ring is a -(5- or        6-membered)heterocycle selected from:

-   -    and    -   (3) when        is ═N—, —NH—, —O—, ═N—(C₁-C₃)alkylene-, —NH—(C₁-C₃)alkylene-,        —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,        —CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-,        —NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,        ═CH—(C₁-C₃)alkylene-N(R¹¹)—, —CH₂—(C₁-C₃)alkylene-N(R¹¹)—,        ═N—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,        —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—,        ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or        —CH₂—O—(C₁-C₃)alkylene-, then the Q_(x) ring is absent;

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,        —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³,        —(CH₂)_(d)—N(R⁹)S(═O)₂T³, or —(CH₂)_(d)S(═O)₂T⁴; and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b)—R¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, 2, 3, and 4;

when s is 1, 2, 3, or 4, each R¹⁰ is independently —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, 3, or 4, each R¹⁰ isindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²) or two R¹⁰ groupsattached to the same carbon atom and are gem-dimethyl, gem-difluoro, ═O,or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

R¹¹ is —H, —CN, or —C(═O)N(R⁶)₂ or R¹ is —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, or —N(R⁶)₂;

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

R¹⁵, when present, is selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₄)alkyl and —O—(C₁-C₄)alkyl, each of which is        unsubstituted or substituted with 1, 2, 3, or 4 independently        selected R⁸ groups;    -   (c) provided that when        is a single bond, a double bond, or —O—, R¹⁵ is not —H;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each T⁴ is independently a -(5- or 6-membered)heteroaryl which isunsubstituted or substituted with 1 or 2 independently selected R¹²groups;

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

Compounds of formula (I^(‡)A) are herein disclosed:

or a pharmaceutically acceptable salt or solvate thereof where:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected R⁷ groups;

each dashed line denotes the presence or absence of a bond (i.e., when adashed line is present there is a double bond at that position and whena dashed line is absent there is only a single bond at that position),provided that:

-   -   (a) one dashed line must denote the presence of a bond (i.e.,        there is a double bond at that position);    -   (b) when one dashed line denotes the presence of a bond (i.e.,        there is a double bond at that position) then the other dashed        line denotes the absence of a bond (i.e., there is only a single        bond at that other position);    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present (i.e., there is a double bond at that position), then R³        is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent (i.e., there is only a single bond at that position),        then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂;

t is an integer selected from 0, 1, 2, and 3;

when t is 0, the Q_(x) ring is a -(3-, 4-, 5-, 6-, or7-membered)heterocycle containing 1, 2, 3, or 4 ring heteroatomsindependently selected from N,N(R⁴), O, and S wherein said heterocycleis unsubstituted or substituted with (R¹⁰)_(s) groups provided that atleast one ring heteroatom is N or N(R⁴) and provided that when thedashed line connecting the Q_(x) ring to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring is present(i.e., there is a double bond at that position), U¹ is C or CH, and

when t is 1, 2, or 3 the Q_(x) ring is a (5- or 6-membered)heterocycleselected from:

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,        —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³;        —(CH₂)_(d)—N(R⁹)S(═O)₂T³; or —(CH₂)_(d)—S(═O)₂T⁴; and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b)—R¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, 2, 3, and 4; when s is 1, 2, 3, or4, each R¹⁰ is independently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, 3,or 4, each R¹⁰ is independently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²) or two R¹⁰ groupsattached to the same carbon atom and are gem-dimethyl, gem-difluoro, ═O,or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each T⁴ is independently a -(5- or 6-membered)heteroaryl which isunsubstituted or substituted with 1 or 2 independently selected R¹²groups;

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

Compounds of formula (IB) are herein disclosed:

or a pharmaceutically acceptable salt or solvate thereof where:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected R⁷ groups;

each dashed line denotes the presence or absence of a bond (i.e., when adashed line is present there is a double bond at that position and whena dashed line is absent there is only a single bond at that position),provided that:

-   -   (a) one dashed line must denote the presence of a bond (i.e.,        there is a double bond at that position);    -   (b) when one dashed line denotes the presence of a bond (i.e.,        there is a double bond at that position) then the other dashed        line denotes the absence of a bond (i.e., there is only a single        bond at that other position);    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present (i.e., there is a double bond at that position), then R³        is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent (i.e., there is only a single bond at that position),        then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and

is ═CH—, —CH₂—, ═N—, —NH—, —O—, ═CH—(C₁-C₃)alkylene-,—CH₂—(C₁-C₃)alkylene-, ═N—(C₁-C₃)alkylene-, —NH—(C₁-C₃)alkylene-,—O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-, —CH₂—(C₂-C₃)alkenylene-,═N—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,═CH—(C₁-C₃)alkylene-N(R¹¹)—, —CH₂—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—,—CH═N—, —CH₂—N(R¹¹)—, ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or—CH₂—O—(C₁-C₃)alkylene-;

each Y is independently O or S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

R¹¹ is —H, —CN, or —C(═O)N(R⁶)₂ or R¹¹ is —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, or —N(R⁶)₂;

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

R¹⁵ is selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₄)alkyl and —O—(C₁-C₄)alkyl, each of which is        unsubstituted or substituted with 1, 2, 3, or 4 independently        selected R⁸ groups;    -   (c) provided that when        is a single bond, a double bond, or —O—, R¹⁵ is not —H;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

A compound of formula (I) and the like or a pharmaceutically acceptablederivative thereof (an “Substituted Benzimidazole-Type PiperidineCompound”) is useful, e.g., as an analgesic, anti-inflammatory,diuretic, anesthetic agent, neuroprotective agent, anti-hypertensive, ananxiolytic agent, an agent for appetite control, hearing regulator,anti-tussive, anti-asthmatic, modulator of locomotor activity, modulatorof learning and memory, regulator of neurotransmitter release, regulatorof hormone release, kidney function modulator, anti-depressant, agent totreat memory loss due to Alzheimer's disease and/or other dementiasand/or disruption of spatial memory, anti-epileptic, anti-convulsant,agent to treat withdrawal from alcohol, agent to treat withdrawal fromdrug(s) of addiction, agent to control water balance, agent to controlsodium excretion, and/or agent to control arterial blood pressuredisorder(s).

A Substituted Benzimidazole-Type Piperidine Compound, a pharmaceuticallyacceptable salt or solvate thereof, a composition containing aSubstituted Benzimidazole-Type Piperidine Compound, and/or a compositioncontaining a pharmaceutically acceptable salt or solvate of aSubstituted Benzimidazole-Type Piperidine Compound is useful fortreating and/or preventing (each hereafter being a “Condition”):

-   -   pain (see, for example: Courteix et al., “Evidence for an        exclusive antinociceptive effect of nociceptin/orphanin FQ, an        endogenous ligand for the ORL1 receptor, in two animal models of        neuropathic pain,” Pain 110:236-245 (2004); Reinscheid et al.,        “Orphanin FQ: a neuropeptide that activates an opioid-like G        protein-coupled receptor,” Science 270:792-794 (1995); Bignan et        al., “Recent advances towards the discovery of ORL-1 receptor        agonists and antagonists,” Expert Opinion on Therapeutic Patents        15(4):357-388 (2005); Meunier et al., “Isolation and structure        of the endogenous agonist of opioid receptor-like ORL1        receptor.” Nature 377:532-535 (1995); Briscini, et al.,        “Up-regulation of ORL-1 receptors in spinal tissue of allodynic        rats after sciatic nerve injury,” Eur. J. Pharmacol. 447:59-65        (2002); Li et al., “Role of nociceptin in the modulation of        nociception in the arcuate nucleus of rats,” Brain Res.        1025:67-74 (2004));

anxiety (see, for example: Jenck et al., “Orphanin FQ acts as ananxiolytic to attenuate behavioral responses to stress,” Proc. Natl.Acad. Sci., U.S.A. 94:14854-14858 (1997); Koster et al., “Targeteddisruption of the orphanin FQ/nociceptin gene increases stresssusceptibility and impairs stress adaptation in mice.” Proc. Natl. Acad.Sci. U.S.A. 96:10444-10449 (1999); Griebel et al., “Orphanin FQ, a novelneuropeptide with anti-stress-like activity,” Brain Res. 836:221-224(1999); Jenck et al., “A synthetic agonist at the orphanin FQ/nociceptinreceptor ORL1: Anxiolytic profile in the rat.” Proc. Natl. Acad. Sci.97:4938-4943 (2000));

cough (see, for example: Fischer et al., “Nociceptin-induced inhibitionof tachykinergic neurotransmission in guinea pig bronchus,” J.Pharmacol. Ther. 285:902-907 (1998); Rizzi et al., “Nociceptin receptoractivation inhibits tachykinergic non adrenergic non cholinergiccontraction of guinea pig isolated bronchus,” Life Sci. 64:L157-L163(1999); Shah et al., “Nociceptin inhibits non-cholinergic contraction inguinea-pig airway,” Br. J. Pharmacol. 125:510-516 (1998); Patel et al.,“Naloxone-insensitive inhibition of acetylcholine release fromparasympathetic nerves innervating guinea-pig trachea by the novelopioid, nociceptin,” Br. J. Pharmacol. 120:735-736 (1997); Helyes etal., “Inhibition by nociceptin of neurogenic inflammation and therelease of SP and CGRP from sensory nerve terminals,” Br. J. Pharmacol.121:613-615 (1997); Nemeth et al., “Inhibition of nociceptin on sensoryneuropeptide release and mast cell-mediated plasma extravasation inrats,” Eur. J. Pharmacol. 347:101-104 (1998); McLeod et al., “Nociceptininhibits cough in the guinea-pig by activation of ORL1 receptors,” Br.J. Pharmacol. 132:1175-1178 (2001); Corboz et al., “Nociceptin inhibitscapsaicin-induced bronchoconstriction in isolated guinea pig lung,” Eur.J. Pharmacol. 402:171-179 (2000));

-   -   gut motility disorders (such as diarrhea and constipation) (see,        for example: Wang et al., “cDNA cloning of an orphan opiate        receptor gene family member and its splice variant,” FEBS Lett.        348:75-79 (1994); Calo' et al., “The mouse deferens: a        pharmacological preparation sensitive to nociceptin,” Eur. J.        Pharmacol. 311:R3-R5 (1996); Zhang et al., “Orphanin FQ has an        inhibitory effect on the guinea pig ileum and the mouse vas        deferens,” Brain Res. 772:102-106 (1997); Osinski et al.,        “Cloning, expression and functional role of a        nociceptin/orphanin FQ receptor in the porcine gastrointestinal        tract,” Eur. J. Pharmacol. 365:281-289 (1999); Yasdani et al.,        “Functional significance of a newly discovered neuropeptide,        orphanin FQ, in rat gastrointestinal motility,” Gastroenterology        116:108-117 ((1999); Corbett et al., “The pharmacological        actions of nociceptin in the isolated colon of rat, mouse, and        man,” Naunyn-Schmiedeberg's Arch. Pharmacol. 358(Suppl 1):4047        (1998); Osinski et al., “Peripheral and central actions of        orphanin FQ (nociceptin) on murine colon,” Am. J. Physiol.        276:G125-G131 (1999); Rizzi et al., “[Nphe¹]nociceptin(1-13)NH₂        antagonizes nociceptin effects in the mouse colon,” Eur. J.        Pharmacol 285:R3-R5 (1999); Taniguchi et al., “The effect of        nociceptin an endogenous ligand for the ORL1 receptor, on rat        colonic contraction and transit,” Eur. J. Pharmacol. 353:265-271        (1998); Pheng et al., “[Nphe¹]nociceptin(1-13)NH₂ selectively        antagonizes nociceptin effects in the rabbit isolated ileum,”        Eur. J. Pharmacol. 397:383-388 (2000));    -   high blood pressure (see, for example: Champion et al.,        “Nociceptin, an endogenous ligand for the ORL1 receptor, has        novel hypotensive activity in the rat,” Life Sci. 60:PL 241-245        (1997); Giuliani et al., “Effect of nociceptin on heart rate and        blood pressure in anaesthetized rats,” Eur. J. Pharmacol.        333:177-179 (1997); Kapusta et al., “Diuretic and        antinatriuretic responses produced by the endogenous opioid-like        peptide, nociceptin (orphanin FQ),” Life Sci. 60:PL15-PL21        (1997); Kapusta et al., “Central administration of        [Phe1psi(CH₂—NH)Gly2]nociceptin(1-13)-NH₂ and orphanin        FQ/nociceptin (OFQ/N) produce similar cardiovascular and renal        responses in conscious rats,” J. Pharmacol. Exp. Ther.        289:173-180 (1999); Madeddu et al., “Cardiovascular effects of        nociceptin in unanaesthetized mice,” Hypertension 33:914-919        (1999); Bigoni et al., “Characterization of nociceptin receptors        in the periphery: in vitro and in vivo studies,”        Naunyn-Schmiedeberg's Arch. Pharmacol. 359:160-167 (1999); Chu        et al., “Inhibition of cardiovascular activity following        microinjection of novel opioid-like neuropeptide nociceptin        (orphanin FQ) into the rat rostral ventrolateral medulla,” Brain        Res. 829:134-142 (1999); Chu et al., “The nociceptin        receptor-mediated inhibition of the rat rostral ventrolateral        medulla neurons in vitro,” Eur. J. Pharmacol. 364:49-53 (1999);        Arndt et al., “Nociceptin/orphanin FQ increases blood pressure        and heart rate via sympathetic activation in sheep,” Peptides        20:465-470 (1999); Gumusel et al., “Nociceptin: an endogenous        agonist for central opioid-like1 (ORL1) receptors possesses        systemic vasorelaxant properties,” Life Sci. 69:PL141-PL145        (1997); Champion et al., “Nociceptin, a novel endogenous ligand        for the ORL1 receptor, dilates isolated resistance arteries from        the rat,” Regul. Peptides 78:69-74 (1998); Czapla et al.,        “Decreases in systemic arterial and hindquarters perfusion        pressure in response to nociceptin are not inhibited by naloxone        in the rat,” Peptides 18:1197-1200 (1997); Armstead,        “Nociceptin/orphanin FQ dilates pial arteries by K(ATP) and        k(ca) channel activation,” Brain Res. 835:315-323 (1999);        Bucher, “ORL1 receptor-mediated inhibition by nociceptin of        noradrenaline release from perivascular sympathetic nerve        endings of the rat tail artery,” Naunyn-Schmiedeberg's Arch.        Pharmacol. 358:682-685 (1998); Champion et al., “Nociceptin, a        novel endogenous ligand for the ORL1 receptor, has potent        erectile activity in the cat,” Am. J. Physiol. 73:E214-E219        (1997));    -   epilepsy (see, for example: Nicol et al., “Nociceptin induced        inhibition of K+ evoked glutamate release from rat        cerebrocortical slices,” Br. J. Pharmacol. 119:1081-1083 (1996);        Nicol et al., “Nociceptin inhibits glutamate release from rat        cerebellar slices,” Br. J. Pharmacol. 123:217 P (1998); Allen et        al., “Orphanin-FQ/nociceptin (OFQ/N) modulates the activity of        suprachiasmatic nucleus neurons,” J. Neurosci. 19:2152-2160        (1999); Faber et al., “Depression of glutamatergic transmission        by nociceptin in the neonatal rat hemisected spinal cord        preparation in vitro,” Br. J. Pharmacol. 119:189-190 (1996);        Vaughn et al., “Actions of the ORL1 receptor ligand nociceptin        on membrane properties of rat periaqueductal gray neurons in        vitro,” J. Neurosci. 17:996-1003 (1997); Wang et al.,        “Nociceptin (orphanin FQ), and endogenous ligand for the ORL1        (opioid receptor-like 1) receptor, modulates responses of        trigeminal neurons evoked by excitatory amino acids and        somatosensory stimuli,” J. Neurophysiol. 76:3568-3572 (1996); Yu        et al., “Orphanin FQ/nociceptin inhibits synaptic transmission        and long-term potentiation in rat dentate gyrus through        postsynaptic mechanisms,” J. Neurophysiol. 80:1277-1284 (1998);        Bregola et al., “Limbic seizures increase pronociceptin mRNA        levels in the thalamic reticular nucleus,” Neuroreport        19:541-546 (1999); Sieklucka-Dziuba et al., “Nociceptin, OP4        receptor ligand in different models of experimental epilepsy,”        Peptides 23:497-505 (2002); Gutierrez, et al., “Orphanin        FQ/nociceptin inhibits kindling epileptogenesis and enhances        hippocampal feed-forward inhibition,” Neuroscience 105:325-333        (2001); Tallent et al., “Nociceptin reduces epileptiform events        in CA3 hippocampus via presynaptic and postsynaptic        mechanisms,” J. Neurosci. 21:6940-6948 (2001));    -   eating-related disorders (such as anorexia/cachexia and obesity)        (see, for example: Pomonis et al., “Orphanin FQ, agonist of        orphan opioid receptor ORL1, stimulates feeding in rats,”        Neuroreport 8:369-371 (1996); Stratford et al., “Injections of        nociceptin into nucleus accumbens shell of ventromedial        hypothalamic nucleus increase food intake,” Neuroreport        8:423-426 (1997); Lee et al., “Nociceptin hyperpolarises        neurones in the rt ventromedial hypothalamus,” Neurosci. Lett.        239:37-40 (1997); Polidori et al., “Sensitivity of brain sites        to the orexigenic effect of nociceptin or of its analog        [Phe]psi(CH₂—NH)Gly2]NC(1-13)NH₂ ,” Regul. Peptides 80:126        (1999); Polidori et al., “Pharmacological characterization of        the nociceptin receptor mediating hyperphagia: identification of        a selective antagonist,” Psychopharmacol. 148:430-437 (2000);        Rowland et al., “The physiology and brain mechanisms of        feeding,” Nutrition 12:626-639 (1996));    -   urinary incontinence (see, for example: Giuliani et al., “The        inhibitory effect of nociceptin on the micturition reflex in        anaesthetized,” Br. J. Pharmacol. 24:1566-1572 (1998); Giuliani        et al., “Nociceptin protects capsaicin-sensitive afferent fibers        in the rat urinary bladder from desensitization,”        Nanyn-Schmiedeberg's Arch. Pharmacol. 360:202-208 (1999); Lecci        et al., “Multiple sites of action in the inhibitory effect of        nociceptin on the micturition reflex,” J. Urology 163:638-645        (2000));    -   renal function (see, for example: Kapusta et al., “Diuretic and        antinatriuretic responses produced by the endogenous opioid-like        peptide, nociceptin (orphanin FQ),” Life Sci. 60:PL15-PL21        (1997); Kapusta et al., “Central administration of        [Phe1psi(CH2-NH)Gly2]nociceptin(1-13)-NH2 and orphanin        FQ/nociceptin (OFQ/N) produce similar cardiovascular and renal        responses in conscious rats,” J. Pharmacol. Exp. Ther.        289:173-180 (1999));

drug abuse (see, for example: Devine et al., “The novel neuropeptideorphanin FQ fails to produce conditioned place preference or aversion,”Brain Res. 727:225-229 (1996); Ciccocioppo et al., “Effect of nociceptinon alcohol intake in alcohol-preferring rats,” Psychopharmacol.141:220-224 (1999); Angeletti et al., “Effect of nociceptin onmorphine-induced conditioned place preference in rats,” RegulatoryPeptides 80:122 (1999); Murphy et al., “Orphanin FQ/nociceptin blocksacquisition of morphine place preference,” Brain Res. 832:168-170(1999); Pieretti et al., “Orphanin FQ effects on morphine-induceddopamine release in the accumbens of rats,” Regulatory Peptides 80:126(1999); Walker et al., “Nociceptin fails to affect heroinself-administration in the rat,” Neuroreport 9:2243-2247 (1998);Narayanan et al., “Orphanin FQ and behavioral sensitization to cocaine,”Pharmacol. Biochem. Behav. 63:271-277 (1999));

memory disorders (see, for example: Sandin et al., “Nociceptin/orphaninFQ microinjected into hippocampus impairs spatial learning in rats,”Eur. J. Neurosci. 9:194-197 (1997); Yu et al., “Orphanin FQ inhibitssynaptic transmission and long-term potentiation in rat hippocampus,”Hippocampus 7:88-94 (1997); Yu et al., “Orphanin FQ/nociceptin inhibitssynaptic transmission and long-term potentiation in rat dentate gyrusthrough postsynaptic mechanisms,” J. Neurophysiol. 80:1277-1284 (1998);Manabe et al., “Facilitation of long-term potentiation and memory inmice lacking nociceptin receptors,” Nature 394:577-581 (1998); Hiramatsuet al., “Effects of nocistatin on nociceptin-induced impairment oflearning and memory in mice,” Eur. J. Pharmacol. 367:151-155 (1999);Mamiya et al., “Nociceptin system plays a role in the memory retention:involvement of naloxone benzoylhydrazone binding sites,” Neuroreport10:1171-1175 (1999); Hiramatsu et al., “Improvement by low doses ofnociceptin on scopolamine-induced impairment of learning and/or memory,”Eur. J. Pharmacol. 395:149-156 (2000));

-   -   depression (see, for example: Rizzi et al., “Nociceptin/orphanin        FQ receptor knockout rats: in vitro and in vivo studies,”        Neuropharmacology 60:572-579 (2011); Goeldner et al.,        “Endogenous nociceptin/orphanin-FQ in the dorsal hippocampus        facilitates despair-related behavior,” Hippocampus 20:911-916        (2010); Vitale et al., “Chronic treatment with the selective NOP        receptor antagonist [Nphe 1, Arg 14, Lys 15]N/OFQ-NH2 (UFP-101)        reverses the behavioural and biochemical effects of        unpredictable chronic mild stress in rats,” Psychopharmacol.        207:173-189 (2009); Zambello et al., “Acute stress        differentially affects corticotropin-releasing hormone mRNA        expression in the central amygdala of the ‘epressed’ finders        sensitive line and the control flinders resistant line rats,”        Prog. Neuro-Psychopharmacol. Biolog. Psychiatry 32:651-661        (2008); Gavioli et al., “Antidepressant-an anxiolytic-like        effects of nociceptin/orphanin FQ receptor ligands,”        Naunyn-Schmiedeberg's Arch. Pharmacol. 372:319-330 (2006);        Gavioli et al., “Blockade of nociceptin/orphanin FQ-NOP receptor        signaling produces antidepressant-like effects: pharmacological        and genetic evidences from the mouse forced swimming test,”        Eur. J. Neurosci. 17:1987-1990 (2003)); and/or    -   dementia or locomotor disorders (such as Parkinsonism) (see, for        example: Reinscheid et al., “Orphanin FQ: a neuropeptide that        activates an opioidlike G protein-coupled receptor,” Science        270:792-794 (1995); Calo' et al., “Characterization of        nociceptin receptors modulating locomotor activity in mice,”        Fund. Clin. Pharmacol. 13:1-27 (1999); Devine et al., “Rats        rapidly develop tolerance to the locomotor-inhibiting effects of        the novel neuropeptide orphanin FQ,” Neurochem. Res.        21:1387-1396 (1996); Noble et al., “Association of        aminopeptidase N and endopeptidase 14.15 inhibitors potentiate        behavioral effects mediated by nociceptin/orphanin FQ in mice,”        FEBS Lett. 401:227-229 (1997); Florin et al., “Nociceptin        stimulates locomotion and exploratory behavior in mice,” Eur. J.        Pharmacol. 317:9-13 (1996)).

For a general discussion of ORL1 receptors see Calo' et al.,“Pharmacology of nociceptin and its receptor: a novel therapeutictarget,” Br. J. Pharmacol. 129:1261-1283 (2000).

Compositions comprising an effective amount of a SubstitutedBenzimidazole-Type Piperidine Compound or a pharmaceutically acceptablesalt or solvate thereof and a pharmaceutically acceptable carrier orexcipient are disclosed. The compositions are useful for treating orpreventing a Condition in an animal.

Methods for treating or preventing a Condition, comprising administeringto an animal in need thereof an effective amount of a SubstitutedBenzimidazole-Type Piperidine Compound, a pharmaceutically acceptablesalt or solvate thereof, a composition containing a SubstitutedBenzimidazole-Type Piperidine Compound, and/or a composition containinga pharmaceutically acceptable salt or solvate of a SubstitutedBenzimidazole-Type Piperidine Compound are disclosed.

Substituted Benzimidazole-Type Piperidine Compounds, e.g., of formula(I), may also be used in the manufacture of a medicament useful fortreating a Condition or for preventing a Condition.

Methods for inhibiting ORL-1 receptor function in a cell, comprisingcontacting a cell capable of expressing the ORL-1 receptor with an ORL-1receptor function-inhibiting amount of a Substituted Benzimidazole-TypePiperidine Compound or a pharmaceutically acceptable salt or solvatethereof are disclosed. In further embodiments of the disclosure, methodsfor activating ORL-1 receptor function in a cell, comprising contactinga cell capable of expressing the ORL-1 receptor with an ORL-1 receptorfunction-activating amount of a Substituted Benzimidazole-TypePiperidine Compound or a pharmaceutically acceptable salt or solvatethereof are disclosed. In yet another embodiment, methods for preparinga composition, comprising the step of admixing a SubstitutedBenzimidazole-Type Piperidine Compound or a pharmaceutically acceptablesalt or solvate thereof and a pharmaceutically acceptable carrier orexcipient, are disclosed.

An embodiment of the disclosure relates to a kit comprising a containercontaining an effective amount of a Substituted Benzimidazole-TypePiperidine Compound or a pharmaceutically acceptable salt or solvatethereof.

Another embodiment of the disclosure provides novel intermediates foruse in making the Substituted Benzimidazole-Type Piperidine Compounds.

The disclosure can be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments of the disclosure.

4. DETAILED DESCRIPTION

The invention includes the following:

(1) A compound of formula (I):

or a pharmaceutically acceptable derivative thereof wherein:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected R⁷ groups;

each dashed line denotes the presence or absence of a bond, providedthat:

-   -   (a) one dashed line must denote the presence of a bond;    -   (b) when one dashed line denotes the presence of a bond then the        other dashed line denotes the absence of a bond ;    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present, then R³ is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent, then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂;

is a single bond, a double bond, ═CH—, —CH₂—, ═N—, —NH—, —O—,═CH—(C₁-C₃)alkylene-, —CH₂—(C₁-C₃)alkylene-, ═N—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,—CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-,—O—(C₂-C₃)alkenylene-, ═CH—(C₁-C₃)alkylene-N(R¹¹)—,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, ═N—(C₁-C₃)alkylene-N(R¹¹)—,—NH—(C₁-C₃)alkylene-N(R¹¹)—, —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—,—CH═N—, —CH₂—N(R¹¹)—, ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or—CH₂—O—(C₁-C₃)alkylene-;

U is:

-   -   (a) —R¹⁵; or    -   (b)

-   -    wherein when        is a single bond or a double bond the Q_(x) ring is a -(4-, 5-,        6-, or 7-membered)heterocycle containing one or two ring        heteroatoms selected from N,N(R⁴), O, and S provided that at        least one ring heteroatom is N or N(R⁴) and wherein either U¹ is        N and U² is a bond or U¹ is C or CH and U² is N or N(R⁴),        provided that;    -   (1) when        is a double bond and the Q_(x) ring is present, U¹ is C; and    -   (2) when        is ═CH—, —CH₂—, ═CH—(C₁-C₃)alkylene-, or —CH₂—(C₁-C₃)alkylene-        and the Q_(x) ring is present, the Q_(x) ring is a        (6-membered)heterocycle selected from:

-   -    and    -   (3) when        is ═N—, —NH—, —O—, ═N—(C₁-C₃)alkylene-, —NH—(C₁-C₃)alkylene-,        —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,        —CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-,        —NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,        ═CH—(C₁-C₃)alkylene-N(R¹¹)—, —CH₂—(C₁-C₃)alkylene-N(R¹¹)—,        ═N—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,        —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—,        ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or        —CH₂—O—(C₁-C₃)alkylene-, then the Q_(x) ring is absent;

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,        —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, or —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³;        and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b)—R¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, and 2;

when s is 1, R¹⁰ is —F, —CH₃, —CH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, the R¹⁰ groups together aregem-dimethyl, gem-difluoro, ═O, or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

R¹¹ is —H, —CN, or —C(═O)N(R⁶)₂ or R¹¹ is —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, or —N(R⁶)₂;

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

R¹⁵, when present, is selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₄)alkyl and —O—(C₁-C₄)alkyl, each of which is        unsubstituted or substituted with 1, 2, 3, or 4 independently        selected R⁸ groups;    -   (c) provided that when        is a single bond, a double bond, or —O—, R¹⁵ is not —H;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and fare each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

(2) The compound of the above (1) which is a compound of formula (IA):

or a pharmaceutically acceptable derivative thereof wherein:

t is an integer selected from 0, 1, 2, and 3;

when t is 0, the Q_(x) ring is a -(4-, 5-, 6-, or 7-membered)heterocyclecontaining one or two ring heteroatoms selected from N,N(R⁴), O, and Sprovided that at least one ring heteroatom is N or N(R⁴) and providedthat when the dashed line connecting the Q_(x) ring to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring is present, U¹is C or CH, and

when t is 1, 2, or 3 the Q_(x) ring is a (6-membered)heterocycleselected from:

(3) The compound of the above (1) which is a compound of formula (IB)

or a pharmaceutically acceptable derivative thereof.

-   -   (4) The compound of any one of the above (1)-(3) or a        pharmaceutically acceptable salt or solvate thereof, wherein        Q_(a) is benzo, pyridino, pyrimidino, pyrazino, or pyridazino,        and preferably Q_(a) is benzo or pyridino, wherein preferably        the 2- and 3-positions of the pyridino are fused to the        5-membered, nitrogen-containing ring.    -   (5) The compound of any one of the above (1)-(4) or a        pharmaceutically acceptable salt or solvate thereof, wherein        Q_(a) is benzo.    -   (6) The compound of any one of the above (1)-(5) or a        pharmaceutically acceptable salt or solvate thereof, wherein a        is 0.    -   (7) The compound of any one of the above (1)-(6) or a        pharmaceutically acceptable salt or solvate thereof, wherein:

Q_(a) is benzo;

a is 0;

A-B together form a (C₂-C₆)bridge, which is unsubstituted or substitutedwith 1, 2, 3, 4, 5, 6, 7 or 8 substituents independently selected from—OH, —(C₁-C₄)alkyl, -halo, and —C(halo)₃, and which bridge optionallycontains —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the A-B bridgecan be in the endo- or exo-configuration with respect to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; and

R¹ is selected from:

-   -   (a) —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂,        —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,        —(C₃-C₁₄)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups.

(8) The compound of any one of the above (1)-(7) or a pharmaceuticallyacceptable salt or solvate thereof, wherein each b is, independently, aninteger selected from 2, 3, and 4.

(9) The compound of any one of the above (1)-(8) or a pharmaceuticallyacceptable salt or solvate thereof, wherein each b is, independently, aninteger selected from 2 and 3.

(10) The compound of any one of the above (1)-(9) or a pharmaceuticallyacceptable salt or solvate thereof, wherein each b is 3.

(11) The compound of any one of the above (1), (2), or (4)-(10) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1 andthe Q_(x) ring is selected from:

(12) The compound of any one of the above (1), (2), or (4)-(11) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, 2,or 3 and the Q_(x) ring is selected from:

(13) The compound of any one of the above (1), (2), or (4)-(12) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1 andthe Q_(x) ring is selected from:

(14) The compound of any one of the above (1), (2), or (4)-(10) or apharmaceutically acceptable salt or solvate thereof, wherein t is 0 andthe Q_(x) ring is selected from:

(15) The compound of any one of the above (1), (2), or (4)-(14) or apharmaceutically acceptable salt or solvate thereof, wherein s is 0.

(16) The compound of any one of the above (1)-(15) or a pharmaceuticallyacceptable salt or solvate thereof, wherein the dashed line within the5-membered, nitrogen-containing ring that is fused to the Q_(a) ring ispresent to provide one bond of a double bond.

(17) The compound of any one of the above (1) or (3)-(10) or apharmaceutically acceptable salt or solvate thereof, wherein ═W— is asingle bond, a double bond, —CH₂—, ═N—, —CH═N—, or —NH—.

(18) The compound of any one of the above (1), (3)-(10), or (17) or apharmaceutically acceptable salt or solvate thereof, wherein R¹⁵ is —OH,—C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.

(19) The compound of any one of the above (1), (3)-(10), (17), or (18)or a pharmaceutically acceptable salt or solvate thereof, wherein ═W— is—CH₂—, ═N—, —CH═N—, or —NH— and R¹⁵ is —C(═O)OH, —C(═O)OCH₃,—C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅,—C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.

(20) The compound of any one of the above (1), (3)-(10), (17), or (18)or a pharmaceutically acceptable salt or solvate thereof, wherein ═W— is—CH₂—, ═N—, —CH═N—, or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂,—CH₂C(═O)OH, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or—C(═NH)NHOCH₃.

(21) The compound of any one of the above (1), (3)-(10), (17), or (18)or a pharmaceutically acceptable salt or solvate thereof, wherein ═W— is—CH₂— or —CH═N— and R¹⁵ is —C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂,—CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅,—OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.

(22) The compound of any one of the above (1), (3)-(10), (17), or (18)or a pharmaceutically acceptable salt or solvate thereof, wherein ═W— is═N— or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.

(23) The compound of any one of the above (1), (3)-(10), (17), or (18)or a pharmaceutically acceptable salt or solvate thereof, wherein ═W— is—CH═N— or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂,—CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅,—OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.

(24) The compound of any one of the above (1)-(3), which is:

or a pharmaceutically acceptable salt or solvate thereof.

(25) The compound of any one of the above (1)-(3) or (24), which is:

or a pharmaceutically acceptable salt or solvate thereof.

(26) The compound of any one of the above (1)-(3), (24), or (25), whichis:

or a pharmaceutically acceptable salt or solvate thereof.

(27) The compound of any one of the above (1)-(23) or a pharmaceuticallyacceptable salt or solvate thereof, wherein h is 1.

(28) The compound of any one of the above (1)-(23) or (27) or apharmaceutically acceptable salt or solvate thereof, wherein Z is—(C₁-C₃)alkyl-optionally substituted by R¹³.

(29) The compound of any one of the above (1)-(28) or a pharmaceuticallyacceptable salt or solvate thereof, wherein R¹³ is absent.

(30) The compound of any one of the above (1)-(23) or (27)-(29) or apharmaceutically acceptable salt or solvate thereof, wherein R¹³ isabsent and Z is —CH₂—CH₂—.

(31) The compound of any one of the above (1)-(23) or (27)-(30) or apharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein each R^(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN andpreferably each R^(z) is independently —H, —CH₃, or —CH₂CH₃.

(32) The compound of any one of the above (1)-(26) or a pharmaceuticallyacceptable salt or solvate thereof, wherein h is 0.

(33) The compound of any one of the above (1)-(23) or (27)-(32) or apharmaceutically acceptable salt or solvate thereof, wherein A and B areindependently —H or —(C₁-C₆)alkyl and preferably A and B are each —H orA is —H and B is —CH₃ or A is —CH₃ and B is —H.

(34) The compound of any one of the above (1)-(32) or a pharmaceuticallyacceptable salt or solvate thereof, wherein A and B together form abridge such that the bridged-piperidine is:

wherein each R^(d) is independently —H, —(C₁-C₄)alkyl, -halo, or—C(halo)₃.

(35) The compound of any one of the above (1)-(32) or (34) or apharmaceutically acceptable salt or solvate thereof, wherein A and Btogether form a bridge such that the bridged-piperidine is:

(36) The compound of any one of the above (1)-(32), (34), or (35) or apharmaceutically acceptable salt or solvate thereof, wherein A and Btogether form a bridge such that the bridged-piperidine is:

(37) The compound of any one of the above (1)-(32) or (34)-(36) or apharmaceutically acceptable salt or solvate thereof, wherein the A-Bbridge of the bridged-piperidine is in the endo-configuration withrespect to the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring.

(38) The compound of any one of the above (1)-(26) or (32)-(37) or apharmaceutically acceptable salt or solvate thereof, wherein:

-   -   (a) h is 0;    -   (b) R¹ is —(C₁-C₁₀)alkyl, —(C₃-C₁₄)cycloalkyl,        —(C₆-C₁₄)cycloalkenyl, —(C₆-C₁₄)bicycloalkyl,        —(C₇-C₁₄)bicycloalkenyl, or —(C₈-C₂₀)tricycloalkyl, each of        which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups and preferably R¹ is        —(C₃-C₁₄)cycloalkyl, -(C₅-C₁₄)cycloalkenyl,        —(C₆-C₁₄)bicycloalkyl, —(C₇-C₁₄)bicycloalkenyl, or        —(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c) each R⁸ is independently —(C₁-C₄)alkyl,        —(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹,        —C(halo)₃, —CH(halo)₂, —CH₂(halo), -halo, —N(R⁹)₂,        —C(═O)N(T¹)(T²), or —C(═O)OR⁹.

(39) The compound of any one of the above (1)-(23) or (32)-(38) or apharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein each R^(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN andpreferably each R^(z) is independently —H, —CH₃, or —CH₂CH₃.

(40) The compound of any one of the above (1)-(23) or (32)-(38) or apharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

(41) The compound of any one of the above (1)-(23) or (32)-(39) or apharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein R^(z) is —H, —CH₃, or —CH₂CH₃.

(42) The compound of any one of the above (1)-(5) or (8)-(41) or apharmaceutically acceptable salt or solvate thereof, wherein a is 1 andR² is -halo, preferably R² is —F.

(43) The compound of any one of the above (1)-(23) or (32)-(38) or apharmaceutically acceptable salt or solvate thereof, wherein the R¹group is in the exo-configuration with respect to the A-B bridge of thebridged piperidine.

(44) A compound which is:

or a pharmaceutically acceptable salt thereof.

(45) The compound of the above (44), which is:

or a pharmaceutically acceptable salt thereof.

(46) The compound of the above (45) having the formula:

or a pharmaceutically acceptable salt thereof.

(47) The compound of any one of the above (1)-(46) or a pharmaceuticallyacceptable salt or solvate thereof, which is radiolabeled.

(48) The compound of any one of the above (1)-(47), wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a para-toluenesulfonic acid-salt.

(49) The compound of any one of the above (1)-(48) or a pharmaceuticallyacceptable salt thereof, wherein the % de of the compound is at leastabout 95%.

(50) The compound of the above (49) or a pharmaceutically acceptablesalt thereof, wherein the % de of the compound is at least about 99%.

(51) A composition comprising an effective amount of the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (1)-(50) and a pharmaceutically acceptable carrier orexcipient.

(52) A method for preparing a composition, comprising the step ofadmixing a compound or a pharmaceutically acceptable salt or solvate ofthe compound of any one of the above (1)-(50) and a pharmaceuticallyacceptable carrier or excipient.

(53) A method for modulating ORL-1 receptor function in a cell,comprising contacting a cell capable of expressing the ORL-1 receptorwith an effective amount of the composition or the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (1)-(51).

(54) The method of the above (53) wherein the composition or thecompound or the pharmaceutically acceptable salt or solvate of thecompound acts as an agonist at the ORL-1 receptor.

(55) The method of the above (53), wherein the composition or thecompound or the pharmaceutically acceptable salt or solvate of thecompound acts as a partial agonist at the ORL-1 receptor.

(56) A method for treating pain in an animal, comprising administeringto an animal in need thereof an effective amount of the composition orthe compound or a pharmaceutically acceptable salt or solvate of thecompound of any one of the above (1)-(51).

(57) A method for treating a memory disorder, obesity, constipation,depression, dementia, Parkinsonism, anxiety, cough, diarrhea, high bloodpressure, epilepsy, anorexia/cachexia, urinary incontinence, or drugabuse in an animal, comprising administering to an animal in needthereof an effective amount of the composition or the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (1)-(51).

(58) Use of a compound or the pharmaceutically acceptable salt orsolvate of the compound of any one of the above (1)-(50) for themanufacture of a medicament useful for treating pain, a memory disorder,obesity, constipation, depression, dementia, Parkinsonism, anxiety,cough, diarrhea, high blood pressure, epilepsy, anorexia/cachexia,urinary incontinence, or drug abuse.

(59) The compound or the pharmaceutically acceptable salt or solvate ofthe compound of any one of the above (1)-(50) for use in the treatmentof pain, a memory disorder, obesity, constipation, depression, dementia,Parkinsonism, anxiety, cough, diarrhea, high blood pressure, epilepsy,anorexia/cachexia, urinary incontinence, or drug abuse.

(60) A kit, comprising a container containing an effective amount of thecomposition or the compound or a pharmaceutically acceptable salt orsolvate of the compound of any one of the above (1)-(51).

(61) The compound of any one of the above (1)-(47) or (49)-(60), whereinthe compound is present as a pharmaceutically acceptable salt.

(62) The compound of any one of the above (1)-(6), (8)-(23), (27)-(30),(32)-(37), (42), (43), or (47)-(61), wherein R¹ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₂-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        5-membered)heterocycle, and -(7-membered)heterocycle, each of        which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups; and    -   (c)

-   -    and    -   (d) -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups.

(63) The compound of any one of the above (1)-(6), (8)-(23), (27), (28),(32)-(37), (42), (43), or (47)-(62), wherein R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₂-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups wherein p is 0 or 1, optionally 0.

(64) The compound of any one of the above (1)-(23), (27)-(43), or(47)-(63), wherein p is 0.

(65) The compound of any one of the above (1), (3)-(10), (16)-(23),(27)-(43), or (47)-(64), wherein R¹⁵, when present, is selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₂)alkyl which is substituted with 1, 2, or 3        independently selected R⁸ groups; and    -   (c) —(C₃-C₄)alkyl and —O—(C₁-C₄)alkyl, each of which is        unsubstituted or substituted with 1, 2, 3, or 4 independently        selected R⁸ groups;    -   (d) provided that when        is a single bond, a double bond, or —O—, R¹ is not —H.

(66) The compound of any one of the above (1)-(23), (27)-(37),(39)-(43), or (47)-(65), wherein each R⁸ is independently —(C₁-C₄)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,—(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, ═N(R⁹), —N₃, —NO₂,—CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹²,—N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹,—C(═O)N(T¹)(T²), —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, or —S(═O)R⁹.

(101) A compound of formula (I^(‡)A):

or a pharmaceutically acceptable salt or solvate thereof where:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected R⁷ groups;

each dashed line denotes the presence or absence of a bond (i.e., when adashed line is present there is a double bond at that position and whena dashed line is absent there is only a single bond at that position),provided that:

-   -   (a) one dashed line must denote the presence of a bond (i.e.,        there is a double bond at that position);    -   (b) when one dashed line denotes the presence of a bond (i.e.,        there is a double bond at that position) then the other dashed        line denotes the absence of a bond (i.e., there is only a single        bond at that other position);    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present (i.e., there is a double bond at that position), then R³        is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent (i.e., there is only a single bond at that position),        then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂;

t is an integer selected from 0, 1, 2, and 3;

when t is 0, the Q_(x) ring is a -(3-, 4-, 5-, 6-, or7-membered)heterocycle containing 1, 2, 3, or 4 ring heteroatomsindependently selected from N,N(R⁴), O, and S wherein said heterocycleis unsubstituted or substituted with (R¹⁰)_(s) groups provided that atleast one ring heteroatom is N or N(R⁴) and provided that when thedashed line connecting the Q_(x) ring to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring is present(i.e., there is a double bond at that position), U¹ is C or CH, and

when t is 1, 2, or 3 the Q_(x) ring is a (5- or 6-membered)heterocycleselected from:

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,        —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³;        —(CH₂)_(d)—N(R⁹)S(═O)₂T³; or —(CH₂)_(d)—S(═O)₂T⁴; and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b)—R¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, 2, 3, and 4;

when s is 1, 2, 3, or 4, each R¹⁰ is independently —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, 3, or 4, each R¹⁰ isindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²) or two R¹⁰ groupsattached to the same carbon atom and are gem-dimethyl, gem-difluoro, ═O,or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁷groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each T⁴ is independently a -(5- or 6-membered)heteroaryl which isunsubstituted or substituted with 1 or 2 independently selected R¹²groups;

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

(102) The compound of the above (101) or a pharmaceutically acceptablesalt or solvate thereof, wherein Q_(a) is benzo, pyridino, pyrimidino,pyrazino, or pyridazino, and preferably Q_(a) is benzo or pyridino,wherein preferably the 2- and 3-positions of the pyridino are fused tothe 5-membered, nitrogen-containing ring.

(103) The compound of the above (101) or (102) or a pharmaceuticallyacceptable salt or solvate thereof, wherein Q_(a) is benzo.

(104) The compound of any one of the above (101)-(103) or apharmaceutically acceptable salt or solvate thereof, wherein a is 0.

(105) The compound of any one of the above (101)-(104) or apharmaceutically acceptable salt or solvate thereof, wherein:

Q_(a) is benzo;

a is 0;

A-B together form a (C₂-C₆)bridge, which is unsubstituted or substitutedwith 1, 2, 3, 4, 5, 6, 7 or 8 substituents independently selected from—OH, —(C₁-C₄)alkyl, -halo, and —C(halo)₃, and which bridge optionallycontains —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the A-B bridgecan be in the endo- or exo-configuration with respect to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; and

R¹ is selected from:

-   -   (a) —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂,        —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,        —(C₃-C₁₄)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups.

(106) The compound of any one of the above (101)-(105) or apharmaceutically acceptable salt or solvate thereof, wherein each b is,independently, an integer selected from 2, 3, and 4.

(107) The compound of any one of the above (101)-(106) or apharmaceutically acceptable salt or solvate thereof, wherein each b is,independently, an integer selected from 2 and 3.

(108) The compound of any one of the above (101)-(107) or apharmaceutically acceptable salt or solvate thereof, wherein each b is3.

(109) The compound of any one of the above (101)-(108) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, 2,or 3, s is 0, 1, or 2, and the Q_(x) ring is selected from:

(110) The compound of any one of the above (101)-(109) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(111) The compound of any one of the above (101)-(108) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(112) The compound of any one of the above (101)-(108) or (111) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(113) The compound of any one of the above (101)-(108) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1 andthe Q, ring is selected from:

(114) The compound of any one of the above (101)-(108) or apharmaceutically acceptable salt or solvate thereof, wherein t is 0, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(115) The compound of any one of the above (101)-(108) or (114) or apharmaceutically acceptable salt or solvate thereof, wherein t is 0, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(116) The compound of any one of the above (101)-(108) or apharmaceutically acceptable salt or solvate thereof, wherein t is 0 andthe Q_(x) ring is selected from:

(117) The compound of any one of the above (101)-(108) or (116) or apharmaceutically pharmaceutically acceptable salt or solvate thereof,wherein t is 0 and the Q_(x) ring is selected from:

(118) The compound of any one of the above (101)-(108), (116), or (117)or a pharmaceutically acceptable salt or solvate thereof, wherein Inanother embodiment, t, is 0 and the Q_(x) ring is selected from:

(119) The compound of any one of the above (101)-(112), (114), or (115)or a pharmaceutically acceptable salt or solvate thereof, wherein s is0.

(120) The compound of any one of the above (101)-(119) or apharmaceutically acceptable salt or solvate thereof, wherein the dashedline within the 5-membered, nitrogen-containing ring that is fused tothe Q_(a) ring is present to provide one bond of a double bond.

(121) The compound of any one of the above (101)-(120) or apharmaceutically acceptable salt or solvate thereof, wherein h is 1.

(122) The compound of any one of the above (101)-(121) or apharmaceutically acceptable salt or solvate thereof, wherein Z is—(C₁-C₃)alkyl-optionally substituted by R¹³.

(123) The compound of any one of the above (101)-(122) or apharmaceutically acceptable salt or solvate thereof, wherein R¹³ isabsent.

(124) The compound of any one of the above (101)-(123) or apharmaceutically acceptable salt or solvate thereof, wherein R¹³ isabsent and Z is —CH₂—CH₂—.

(125) The compound of any one of the above (101)-(124) or apharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein each R^(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN andpreferably each R^(z) is independently —H, —CH₃, or —CH₂CH₃.

(126) The compound of any one of the above (101)-(120) or apharmaceutically acceptable salt or solvate thereof, wherein h is 0.

(127) The compound of any one of the above (101)-(126) or apharmaceutically acceptable salt or solvate thereof, wherein A and B areindependently —H or —(C₁-C₆)alkyl and preferably A and B are each —H orA is —H and B is —CH₃ or A is —CH₃ and B is —H.

(128) The compound of any one of the above (101)-(126) or apharmaceutically acceptable salt or solvate thereof, wherein A and Btogether form a bridge such that the bridged-piperidine is:

wherein each R^(d) is independently —H, —(C₁-C₄)alkyl, -halo, or—C(halo)₃.

(129) The compound of any one of the above (101)-(126) or (128) or apharmaceutically acceptable salt or solvate thereof, wherein A and Btogether form a bridge such that the bridged-piperidine is:

(130) The compound of any one of the above (101)-(126), (128), or (129)or a pharmaceutically acceptable salt or solvate thereof, wherein A andB together form a bridge such that the bridged-piperidine is:

(131) The compound of any one of the above (101)-(126) or (128)-(130) ora pharmaceutically acceptable salt or solvate thereof, wherein the A-Bbridge of the bridged-piperidine is in the endo-configuration withrespect to the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring.

(132) The compound of any one of the above (101)-(120) or (126)-(131) ora pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   (a) h is 0;    -   (b) R¹ is —(C₁-C₁₀)alkyl, —(C₃-C₁₄)cycloalkyl,        —(C₅-C₁₄)cycloalkenyl, —(C₆-C₁₄)bicycloalkyl,        —(C₇-C₁₄)bicycloalkenyl, or -(C₈-C₂₀)tricycloalkyl, each of        which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups and preferably R¹ is        —(C₃-C₁₄)cycloalkyl, -(C₅-C₁₄)cycloalkenyl,        —(C₆-C₁₄)bicycloalkyl, —(C₇-C₁₄)bicycloalkenyl, or        —(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c) each R⁸ is independently —(C₁-C₄)alkyl,        —(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹,        —C(halo)₃, —CH(halo)₂, —CH₂(halo), -halo, —N(R⁹)₂,        —C(═O)N(T¹)(T²), or —C(═O)OR⁹.

(133) The compound of any one of the above (101)-(120) or (126)-(132) ora pharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein each R^(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN andpreferably each R^(z) is independently —H, —CH₃, or —CH₂CH₃.

(134) The compound of any one of the above (101)-(120) or (126)-(132) ora pharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

(135) The compound of any one of the above (101)-(120) or (126)-(133) ora pharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein R^(z) is —H, —CH₃, or —CH₂CH₃.

(136) The compound of any one of the above (101)-(103) or (106)-(135) ora pharmaceutically acceptable salt or solvate thereof, wherein a is 1and R² is -halo, preferably R² is —F.

(137) The compound of any one of the above (101)-(120) or (126)-(136) ora pharmaceutically acceptable salt or solvate thereof, wherein the R¹group is in the exo-configuration with respect to the A-B bridge of thebridged piperidine.

(138) The compound of any one of the above (101)-(104), (106)-(124),(126)-(132), (136), or (137) or a pharmaceutically acceptable salt orsolvate thereof, wherein R¹ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₂-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        5-membered)heterocycle, and -(7-membered)heterocycle, each of        which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups; and    -   (c)

-   -    and    -   (d) -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups.

(139) The compound of any one of the above (101)-(104), (106)-(122),(126)-(131), or (136) or a pharmaceutically acceptable salt or solvatethereof, wherein R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₂-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups.

(140) The compound of any one of the above (101)-(139) or apharmaceutically acceptable salt or solvate thereof, which isradiolabeled.

(141) The compound of any one of the above (101)-(140), wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a para-toluenesulfonic acid-salt.

(142) The compound of any one of the above (101)-(141) or apharmaceutically acceptable salt thereof, wherein the % de of thecompound is at least about 95%.

(143) The compound of the above (142) or a pharmaceutically acceptablesalt thereof, wherein the % de of the compound is at least about 99%.

(144) A composition comprising an effective amount of the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (101)-(143) and a pharmaceutically acceptable carrier orexcipient.

(145) A method for preparing a composition, comprising the step ofadmixing a compound or a pharmaceutically acceptable salt or solvate ofthe compound of any one of the above (101)-(143) and a pharmaceuticallyacceptable carrier or excipient.

(146) A method for modulating ORL-1 receptor function in a cell,comprising contacting a cell capable of expressing the ORL-1 receptorwith an effective amount of the composition or the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (101)-(144).

(147) The method of the above (146) wherein the composition or thecompound or the pharmaceutically acceptable salt or solvate of thecompound acts as an agonist at the ORL-1 receptor.

(148) The method of the above (146), wherein the composition or thecompound or the pharmaceutically acceptable salt or solvate of thecompound acts as a partial agonist at the ORL-1 receptor.

(149) A method for treating pain in an animal, comprising administeringto an animal in need thereof an effective amount of the composition orthe compound or a pharmaceutically acceptable salt or solvate of thecompound of any one of the above (101)-(144).

(150) A method for treating a memory disorder, obesity, constipation,depression, dementia, Parkinsonism, anxiety, cough, diarrhea, high bloodpressure, epilepsy, anorexia/cachexia, urinary incontinence, or drugabuse in an animal, comprising administering to an animal in needthereof an effective amount of the composition or the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (101)-(144).

(151) Use of a compound or the pharmaceutically acceptable salt orsolvate of the compound of any one of the above (101)-(143) for themanufacture of a medicament useful for treating pain, a memory disorder,obesity, constipation, depression, dementia, Parkinsonism, anxiety,cough, diarrhea, high blood pressure, epilepsy, anorexia/cachexia,urinary incontinence, or drug abuse.

(152) The compound or the pharmaceutically acceptable salt or solvate ofthe compound of any one of the above (101)-(143) for use in thetreatment of pain, a memory disorder, obesity, constipation, depression,dementia, Parkinsonism, anxiety, cough, diarrhea, high blood pressure,epilepsy, anorexia/cachexia, urinary incontinence, or drug abuse.

(153) A kit, comprising a container containing an effective amount ofthe composition or the compound or a pharmaceutically acceptable salt orsolvate of the compound of any one of the above (101)-(144).

(154) The compound of any one of the above (101)-(140) or (142)-(153),wherein the compound is present as a pharmaceutically acceptable salt.

(200) A compound of formula (I*)

or a pharmaceutically acceptable salt or solvate thereof wherein:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected R⁷ groups;

each dashed line denotes the presence or absence of a bond, providedthat:

-   -   (a) one dashed line must denote the presence of a bond;    -   (b) when one dashed line denotes the presence of a bond then the        other dashed line denotes the absence of a bond;    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present, then R³ is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent, then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂,

is a single bond, a double bond, ═CH—, —CH₂—, ═N—, —NH—, —O—,═CH—(C₁-C₃)alkylene-, —CH₂—(C₁-C₃)alkylene-, ═N—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,—CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-,—O—(C₂-C₃)alkenylene-, ═CH—(C₁-C₃)alkylene-N(R¹¹)—,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, ═N—(C₁-C₃)alkylene-N(R¹¹)—,—NH—(C₁-C₃)alkylene-N(R¹¹)—, —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—,—CH═N—, —CH₂—N(R¹¹)—, ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or—CH₂—O—(C₁-C₃)alkylene-;

U is:

-   -   (a) —R¹⁵; or    -   (b)

-   -    wherein when        is a single bond or a double bond the Q_(x) ring is a -(3-, 4-,        5-, 6-, or 7-membered)heterocycle containing 1, 2, 3, or 4 ring        heteroatoms independently selected from N,N(R⁴), O, and S,        wherein said heterocycle is unsubstituted or substituted with        (R¹⁰)_(s), provided that at least one ring heteroatom is N or        N(R⁴) and wherein either U¹ is N and U² is a bond or U¹ is C or        CH and U² is N or N(R⁴), provided that;    -   (1) when        is a double bond and the Q_(x) ring is present, U¹ is C; and    -   (2) when        is ═CH—, —CH₂—, ═CH—(C₁-C₃)alkylene-, or —CH₂—(C₁-C₃)alkylene-        and the Q_(x) ring is present, the Q_(x) ring is a -(5- or        6-membered)heterocycle selected from:

and

-   -   (3) when        is ═N—, —NH—, —O—, ═N—(C₁-C₃)alkylene-, —NH—(C₁-C₃)alkylene-,        —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,        —CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-,        —NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,        ═CH—(C₁-C₃)alkylene-N(R¹¹)—, —CH₂—(C₁-C₃)alkylene-N(R¹¹)—,        ═N—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,        —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—,        ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or        —CH₂—O—(C₁-C₃)alkylene-, then the Q_(x) ring is absent;

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,        —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³,        —(CH₂)_(d)—N(R⁹)S(═O)₂T³, or —(CH₂)_(d)S(═O)₂T⁴; and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b)—R¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, 2, 3, and 4;

when s is 1, 2, 3, or 4, each R¹⁰ is independently —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, 3, or 4, each R¹⁰ isindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²) or two R¹⁰ groupsattached to the same carbon atom and are gem-dimethyl, gem-difluoro, ═O,or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

R¹¹ is —H, —CN, or —C(═O)N(R⁶)₂ or R¹¹ is —(C₁-C₄)alkyl which isunsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, or —N(R⁶)₂;

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

R¹⁵, when present, is selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₄)alkyl and —O—(C₁-C₄)alkyl, each of which is        unsubstituted or substituted with 1, 2, 3, or 4 independently        selected R⁸ groups;    -   (c) provided that when        is a single bond, a double bond, or —O—, R¹⁵ is not —H;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each T⁴ is independently a -(5- or 6-membered)heteroaryl which isunsubstituted or substituted with 1 or 2 independently selected R¹²groups;

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

(201) A compound of formula (I^(‡)A):

or a pharmaceutically acceptable salt or solvate thereof where:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected R⁷ groups;

each dashed line denotes the presence or absence of a bond (i.e., when adashed line is present there is a double bond at that position and whena dashed line is absent there is only a single bond at that position),provided that:

-   -   (a) one dashed line must denote the presence of a bond (i.e.,        there is a double bond at that position);    -   (b) when one dashed line denotes the presence of a bond (i.e.,        there is a double bond at that position) then the other dashed        line denotes the absence of a bond (i.e., there is only a single        bond at that other position);    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present (i.e., there is a double bond at that position), then R³        is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent (i.e., there is only a single bond at that position),        then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂;

t is an integer selected from 0, 1, 2, and 3;

when t is 0, the Q_(x) ring is a -(3-, 4-, 5-, 6-, or7-membered)heterocycle containing 1, 2, 3, or 4 ring heteroatomsindependently selected from N,N(R⁴), O, and S wherein said heterocycleis unsubstituted or substituted with (R¹⁰)_(s) provided that at leastone ring heteroatom is N or N(R⁴) and provided that when the dashed lineconnecting the Q_(x) ring to the 5-membered, nitrogen-containing ringthat is fused to the Q_(a) ring is present (i.e., there is a double bondat that position), U¹ is C or CH, and

when t is 1, 2, or 3 the Q_(x) ring is a (5- or 6-membered)heterocycleselected from:

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,        —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³;        —(CH₂)_(d)—N(R⁹)S(═O)₂T³; or —(CH₂)_(d)—S(═O)₂T⁴; and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b)—R¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, 2, 3, and 4;

when s is 1, 2, 3, or 4, each R¹⁰ is independently —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, 3, or 4, each R¹⁰ isindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(ad)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²) or two R¹⁰ groupsattached to the same carbon atom and are gem-dimethyl, gem-difluoro, ═O,or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each T¹ and T² is independently —H or —(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any —(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each T⁴ is independently a -(5- or 6-membered)heteroaryl which isunsubstituted or substituted with 1 or 2 independently selected R¹²groups;

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and fare each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

(202) The compound of the above (200) or (201) or a pharmaceuticallyacceptable salt or solvate thereof, wherein Q_(a) is benzo, pyridino,pyrimidino, pyrazino, or pyridazino, and preferably Q_(a) is benzo orpyridino, wherein preferably the 2- and 3-positions of the pyridino arefused to the 5-membered, nitrogen-containing ring.

(203) The compound of the above (200) or (202) or a pharmaceuticallyacceptable salt or solvate thereof, wherein Q_(a) is benzo.

(204) The compound of any one of the above (200)-(203) or apharmaceutically acceptable salt or solvate thereof, wherein a is 0.

(205) The compound of any one of the above (200)-(204) or apharmaceutically acceptable salt or solvate thereof, wherein:

Q_(a) is benzo;

a is 0;

A-B together form a (C₂-C₆)bridge, which is unsubstituted or substitutedwith 1, 2, 3, 4, 5, 6, 7 or 8 substituents independently selected from—OH, —(C₁-C₄)alkyl, -halo, and —C(halo)₃, and which bridge optionallycontains —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the A-B bridgecan be in the endo- or exo-configuration with respect to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring;

Z is —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; and

R¹ is selected from:

-   -   (a) —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂,        —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,        —(C₃-C₁₄)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups.

(206) The compound of any one of the above (200)-(205) or apharmaceutically acceptable salt or solvate thereof, wherein each b is,independently, an integer selected from 2, 3, and 4.

(207) The compound of any one of the above (200)-(206) or apharmaceutically acceptable salt or solvate thereof, wherein each b is,independently, an integer selected from 2 and 3.

(208) The compound of any one of the above (200)-(207) or apharmaceutically acceptable salt or solvate thereof, wherein each b is3.

(209) The compound of any one of the above (200)-(208) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, 2,or 3, s is 0, 1, or 2, and the Q_(x) ring is selected from:

(210) The compound of any one of the above (201)-(209) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(211) The compound of any one of the above (201)-(208) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(212) The compound of any one of the above (200)-(208) or (211) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(213) The compound of any one of the above (200)-(208) or apharmaceutically acceptable salt or solvate thereof, wherein t is 1 andthe Q_(x) ring is selected from:

(214) The compound of any one of the above (200)-(208) or apharmaceutically acceptable salt or solvate thereof, wherein t is 0, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(215) The compound of any one of the above (200)-(208) or (214) or apharmaceutically acceptable salt or solvate thereof, wherein t is 0, sis 0, 1, or 2, and the Q_(x) ring is selected from:

(216) The compound of any one of the above (200)-(208) or apharmaceutically acceptable salt or solvate thereof, wherein t is 0 andthe Q_(x) ring is selected from:

(217) The compound of any one of the above (200)-(208) or (216) or apharmaceutically acceptable salt or solvate thereof, wherein t is 0 andthe Q_(x) ring is selected from:

(218) The compound of any one of the above (200)-(208), (216), or (217)or a pharmaceutically acceptable salt or solvate thereof, wherein Inanother embodiment, t is 0 and the Q_(x) ring is selected from:

(219) The compound of any one of the above (200)-(212), (214), or (215)or a pharmaceutically acceptable salt or solvate thereof, wherein s is0.

(220) The compound of any one of the above (200)-(219) or apharmaceutically acceptable salt or solvate thereof, wherein the dashedline within the 5-membered, nitrogen-containing ring that is fused tothe Q_(a) ring is present to provide one bond of a double bond.

(221) The compound of any one of the above (200)-(220) or apharmaceutically acceptable salt or solvate thereof, wherein h is 1.

(222) The compound of any one of the above (200)-(221) or apharmaceutically acceptable salt or solvate thereof, wherein Z is—(C₁-C₃)alkyl-optionally substituted by R¹³.

(223) The compound of any one of the above (200)-(222) or apharmaceutically acceptable salt or solvate thereof, wherein R¹³ isabsent.

(224) The compound of any one of the above (200)-(223) or apharmaceutically acceptable salt or solvate thereof, wherein R¹³ isabsent and Z is —CH₂—CH₂—.

(225) The compound of any one of the above (200)-(224) or apharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein each R^(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN andpreferably each R^(z) is independently —H, —CH₃, or —CH₂CH₃.

(226) The compound of any one of the above (200)-(220) or apharmaceutically acceptable salt or solvate thereof, wherein h is 0.

(227) The compound of any one of the above (200)-(226) or apharmaceutically acceptable salt or solvate thereof, wherein A and B areindependently —H or —(C₁-C₆)alkyl and preferably A and B are each —H orA is —H and B is —CH₃ or A is —CH₃ and B is —H.

(228) The compound of any one of the above (200)-(226) or apharmaceutically acceptable salt or solvate thereof, wherein A and Btogether form a bridge such that the bridged-piperidine is:

wherein each R^(d) is independently —H, —(C₁-C₄)alkyl, -halo, or—C(halo)₃.

(229) The compound of any one of the above (200)-(226) or (228) or apharmaceutically acceptable salt or solvate thereof, wherein A and Btogether form a bridge such that the bridged-piperidine is:

(230) The compound of any one of the above (200)-(226), (228), or (229)or a pharmaceutically acceptable salt or solvate thereof, wherein A andB together form a bridge such that the bridged-piperidine is:

(231) The compound of any one of the above (200)-(226) or (228)-(230) ora pharmaceutically acceptable salt or solvate thereof, wherein the A-Bbridge of the bridged-piperidine is in the endo-configuration withrespect to the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring.

(232) The compound of any one of the above (200)-(220) or (226)-(231) ora pharmaceutically acceptable salt or solvate thereof, wherein:

-   -   (a) h is 0;    -   (b) R¹ is —(C₁-C₁₀)alkyl, —(C₃-C₁₄)cycloalkyl,        —(C₅-C₁₄)cycloalkenyl, —(C₆-C₁₄)bicycloalkyl,        —(C₇-C₁₄)bicycloalkenyl, or —(C₈-C₂₀)tricycloalkyl, each of        which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups and preferably R¹ is        —(C₃-C₁₄)cycloalkyl, —(C₅-C₁₄)cycloalkenyl,        —(C₆-C₁₄)bicycloalkyl, —(C₇-C₁₄)bicycloalkenyl, or        -(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c) each R⁸ is independently —(C₁-C₄)alkyl,        —(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹,        —C(halo)₃, —CH(halo)₂, —CH₂(halo), -halo, —N(R⁹)₂,        —C(═O)N(T¹)(T²), or —C(═O)OR⁹.

(233) The compound of any one of the above (200)-(220) or (226)-(232) ora pharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein each R^(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN andpreferably each R^(z) is independently —H, —CH₃, or —CH₂CH₃.

(234) The compound of any one of the above (200)-(220) or (226)-(232) ora pharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

(235) The compound of any one of the above (200)-(220) or (226)-(233) ora pharmaceutically acceptable salt or solvate thereof, wherein —Z—R¹ is:

wherein R^(z) is —H, —CH₃, or —CH₂CH₃.

(236) The compound of any one of the above (200)-(203) or (206)-(235) ora pharmaceutically acceptable salt or solvate thereof, wherein a is 1and R² is -halo, preferably R² is —F.

(237) The compound of any one of the above (200)-(220) or (226)-(236) ora pharmaceutically acceptable salt or solvate thereof, wherein the R¹group is in the exo-configuration with respect to the A-B bridge of thebridged piperidine.

(238) The compound of any one of the above (200)-(204), (206)-(224),(226)-(232), (236), or (237) or a pharmaceutically acceptable salt orsolvate thereof, wherein R¹ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₂-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        5-membered)heterocycle, and -(7-membered)heterocycle, each of        which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups; and    -   (c)

-   -    and    -   (d) -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups.

(239) The compound of any one of the above (200)-(204), (206)-(222),(226)-(231), or (236) or a pharmaceutically acceptable salt or solvatethereof, wherein R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₂-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

and

(d) -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁷ groups.

(240) The compound of any one of the above (200)-(239) or apharmaceutically acceptable salt or solvate thereof, which isradiolabeled.

(241) The compound of any one of the above (200)-(240), wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a para-toluenesulfonic acid-salt.

(242) The compound of any one of the above (200)-(241) or apharmaceutically acceptable salt thereof, wherein the % de of thecompound is at least about 95%.

(243) The compound of the above (242) or a pharmaceutically acceptablesalt thereof, wherein the % de of the compound is at least about 99%.

(244) A composition comprising an effective amount of the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (200)-(243) and a pharmaceutically acceptable carrier orexcipient.

(245) A method for preparing a composition, comprising the step ofadmixing a compound or a pharmaceutically acceptable salt or solvate ofthe compound of any one of the above (200)-(243) and a pharmaceuticallyacceptable carrier or excipient.

(246) A method for modulating ORL-1 receptor function in a cell,comprising contacting a cell capable of expressing the ORL-1 receptorwith an effective amount of the composition or the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (200)-(244).

(247) The method of the above (246) wherein the composition or thecompound or the pharmaceutically acceptable salt or solvate of thecompound acts as an agonist at the ORL-1 receptor.

(248) The method of the above (246), wherein the composition or thecompound or the pharmaceutically acceptable salt or solvate of thecompound acts as a partial agonist at the ORL-1 receptor.

(249) A method for treating pain in an animal, comprising administeringto an animal in need thereof an effective amount of the composition orthe compound or a pharmaceutically acceptable salt or solvate of thecompound of any one of the above (200)-(244).

(250) A method for treating a memory disorder, obesity, constipation,depression, dementia, Parkinsonism, anxiety, cough, diarrhea, high bloodpressure, epilepsy, anorexia/cachexia, urinary incontinence, or drugabuse in an animal, comprising administering to an animal in needthereof an effective amount of the composition or the compound or apharmaceutically acceptable salt or solvate of the compound of any oneof the above (200)-(244).

(251) Use of a compound or the pharmaceutically acceptable salt orsolvate of the compound of any one of the above (200)-(243) for themanufacture of a medicament useful for treating pain, a memory disorder,obesity, constipation, depression, dementia, Parkinsonism, anxiety,cough, diarrhea, high blood pressure, epilepsy, anorexia/cachexia,urinary incontinence, or drug abuse.

(252) The compound or the pharmaceutically acceptable salt or solvate ofthe compound of any one of the above (200)-(243) for use in thetreatment of pain, a memory disorder, obesity, constipation, depression,dementia, Parkinsonism, anxiety, cough, diarrhea, high blood pressure,epilepsy, anorexia/cachexia, urinary incontinence, or drug abuse.

(253) A kit, comprising a container containing an effective amount ofthe composition or the compound or a pharmaceutically acceptable salt orsolvate of the compound of any one of the above (200)-(244).

(254) The compound of any one of the above (200)-(240) or (242)-(253),wherein the compound is present as a pharmaceutically acceptable salt.

4.1 SUBSTITUTED BENZIMIDAZOLE-TYPE PIPERIDINE COMPOUNDS OF FORMULA (I)

Compounds of formula (I) are herein disclosed:

or a pharmaceutically acceptable derivative thereof where each dashedline, Q_(a), R¹, R², R³, A, B, U, W, Z, and a are defined above for theSubstituted Benzimidazole-Type Piperidine Compounds of Formula (I).

In one embodiment, a is 0 or 1. In another embodiment, a is 0. Inanother embodiment, a is 1. In another embodiment, a is 2.

In another embodiment, each R² is independently -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl.

In another embodiment, a is 1 and R² is -halo, —OH, —NH₂, —CN,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or 6-membered)heterocycle,-phenyl, -naphthalenyl, or -(5- or 6-membered)heteroaryl. In anotherembodiment, a is 1 and R² is -halo, —OH, —NH₂, —CN, methyl, ethyl,n-propyl, iso-propyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl.In another embodiment, a is 1 and R² is -halo. In another embodiment, ais 1 and R² is —F or —Cl. In another embodiment, a is 1 and R² is —F. Inanother embodiment, a is 1 and R² is —Cl.

In another embodiment, a is 2 and each R² is independently -halo, —OH,—NH₂, —CN, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -(5- or6-membered)heterocycle, -phenyl, -naphthalenyl, or -(5- or6-membered)heteroaryl. In another embodiment, a is 2 and each R² isindependently -halo, —OH, —NH₂, —CN, methyl, ethyl, n-propyl,iso-propyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl. In anotherembodiment, a is 2 and each R² is -halo. In another embodiment, a is 2and each R² is —F or —Cl. In another embodiment, a is 2 and each R² is—F. In another embodiment, a is 2 and each R² is —Cl.

In another embodiment, the compound of formula (I) is a compound offormula (I′):

or a pharmaceutically acceptable salt or solvate thereof where —W— is asingle bond, —CH₂—, —NH—, —O—, —CH₂—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,—CH₂—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,—O—(C₁-C₃)alkylene-N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—, —CH₂—O—, or—CH₂—O—(C₁-C₃)alkylene- and Q_(a), R¹, R², R¹¹, A, B, U, Z, and a are asdefined for the compounds of formula (I).

In another embodiment, the compound of formula (I) is a compound offormula (I″):

or a pharmaceutically acceptable salt or solvate thereof where ═W— is adouble bond, ═CH—, ═N—, ═CH—(C₁-C₃)alkylene-, ═N—(C₁-C₃)alkylene-,═CH—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-,═CH—(C₁-C₃)alkylene-N(R¹¹)—, ═N—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—,═CH—O—, OR═CH—O—(C₁-C₃)alkylene- and Q_(a), R¹, R², R³, R¹¹, A, B, U, Z,and a are as defined for the compounds of formula (I).

In another embodiment, Q_(a) is benzo, pyridino, pyrimidino, pyrazino,pyridazino, pyrrolino, imidazolino, pyrazolino, triazolino, furano,oxazolino, isoxazolino, oxadiazolino, thiopheno, thiazolino,isothiazolino, or thiadiazolino. In another embodiment, Q_(a) is benzo,pyrrolino, imidazolino, pyrazolino, triazolino, furano, oxazolino,isoxazolino, oxadiazolino, thiopheno, thiazolino, isothiazolino, orthiadiazolino. In another embodiment, Q_(a) is benzo, imidazolino,pyrazolino, triazolino, oxazolino, isoxazolino, oxadiazolino,thiazolino, isothiazolino, or thiadiazolino. In another embodiment,Q_(a) is benzo, pyrrolino, imidazolino, pyrazolino, or triazolino. Inanother embodiment, Q_(a) is benzo, furano, oxazolino, isoxazolino, oroxadiazolino. In another embodiment, Q_(a) is benzo, oxazolino,isoxazolino, or oxadiazolino. In another embodiment, Q_(a) is benzo,thiopheno, thiazolino, isothiazolino, or thiadiazolino. In anotherembodiment, Q_(a) is benzo, thiazolino, isothiazolino, or thiadiazolino.In another embodiment, Q_(a) is benzo, pyrrolino, furano, or thiopheno.In another embodiment, Q_(a) is pyridino, pyrimidino, pyrazino,pyridazino, pyrrolino, imidazolino, pyrazolino, triazolino, furano,oxazolino, isoxazolino, oxadiazolino, thiopheno, thiazolino,isothiazolino, or thiadiazolino. In another embodiment, Q_(a) ispyrrolino, imidazolino, pyrazolino, triazolino, furano, oxazolino,isoxazolino, oxadiazolino, thiopheno, thiazolino, isothiazolino, orthiadiazolino. In another embodiment, Q_(a) is imidazolino, pyrazolino,triazolino, oxazolino, isoxazolino, oxadiazolino, thiazolino,isothiazolino, or thiadiazolino. In another embodiment, Q_(a) ispyrrolino, imidazolino, pyrazolino, or triazolino. In anotherembodiment, Q_(a) is furano, oxazolino, isoxazolino, or oxadiazolino. Inanother embodiment, Q_(a) is oxazolino, isoxazolino, or oxadiazolino. Inanother embodiment, Q_(a) is thiopheno, thiazolino, isothiazolino, orthiadiazolino. In another embodiment, Q_(a) is thiazolino,isothiazolino, or thiadiazolino. In another embodiment, Q_(a) ispyrrolino, furano, or thiopheno. In another embodiment, Q_(a) is benzo,pyridino, pyrimidino, pyrazino, or pyridazino. In another embodiment,Q_(a) is benzo, pyrimidino, pyrazino, or pyridazino. In anotherembodiment, Q_(a) is pyridino, pyrimidino, pyrazino, or pyridazino. Inanother embodiment, Q_(a) is pyrimidino, pyrazino, or pyridazino. Inanother embodiment, Q_(a) is benzo or pyridino. In another embodiment,Q_(a) is benzo. In another embodiment, Q_(a) is pyridino.

In another embodiment, a is 1, Q_(a) is benzo or pyridino, and R² isattached at the position shown below, denoted for purposes of theR²-attachment-position herein as the “6-position”, of the benzo orpyridino, e.g., as illustrated below:

In another embodiment, a is 1, Q_(a) is benzo or pyridino, R² is -halo,and R² is attached at the 6-position of the benzo or pyridino asillustrated immediately above. In another embodiment, a is 1, Q_(a) isbenzo or pyridino, R² is —F or —Cl, and R² is attached at the 6-positionof the benzo or pyridino as illustrated immediately above. In anotherembodiment, a is 1, Q_(a) is benzo or pyridino, R² is —F, and R² isattached at the 6-position of the benzo or pyridino as illustratedimmediately above.

In another embodiment, Q_(a) is benzo. In another embodiment, Q_(a) ispyridino. In another embodiment, Q_(a) is pyridino and the 2- and3-positions of the pyridino are fused to the 6-membered,nitrogen-containing ring as illustrated, inter alia, for compoundsaccording to Formula (I) in Table 1 and for compounds according toFormula (IB) in Table 17, and the like.

In another embodiment, each R⁷ is independently selected from—(C₁-C₄)alkyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), -halo,—N(R⁹)₂, —N(R⁹)C(═O)OR¹², —C(═O)OR⁹, and —OC(═O)R⁹. In anotherembodiment, each R⁷ is independently selected from —(C₁-C₄)alkyl, —OR⁹,—C(halo)₃, —CH(halo)₂, —CH₂(halo), -halo, —N(R⁹)₂, —C(═O)OR⁹, and—OC(═O)R⁹. In another embodiment, each R⁷ is independently selected from—(C₁-C₄)alkyl, —OR⁹, —C(halo)₃, -halo, —N(R⁹)₂, and —C(═O)OR⁹.

In another embodiment, each R⁸ is independently selected from—(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O,═S, ═N(R⁹), -halo, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),OC(═O)OR⁹, —S(═O)R⁹, and —S(═O)₂R⁹. In another embodiment, each R⁸ isindependently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═N(R⁹), -halo, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²),—N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹,—OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, and —S(═O)₂R⁹. In anotherembodiment, each R⁸ is independently selected from —(C₁-C₄)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,—(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, ═N(R⁹), —NO₂, —CH═N(R⁹),—N(R⁹)₂, —N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, and—S(═O)₂R⁹. In another embodiment, each R⁸ is independently selected from—(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,═N(R), -halo, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, and —S(═O)₂R⁹. In another embodiment, each R⁸ isindependently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═N(R⁹), —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²),—N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹,—OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, and —S(═O)₂R⁹. In anotherembodiment, each R⁸ is independently selected from —(C₁-C₄)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,—(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, ═N(R⁹), —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)R⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, and—S(═O)₂R⁹.

In another embodiment, each R⁸ is independently selected from—(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,═N(R⁹), —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, and —S(═O)₂R⁹.

In another embodiment, each R⁸ is independently selected from—(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —S(═O)R⁹, and —S(═O)₂R⁹. In another embodiment,each R⁸ is independently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,-(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), ═O, ═S, ═N(R⁹), -halo, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²),—N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹,—S(═O)R⁹, and —S(═O)₂R⁹. In another embodiment, each R⁸ is independentlyselected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), -halo, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹, —N(R⁹)S(═O)₂R¹²,—N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹,—C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, and —S(═O)₂R⁹. In anotherembodiment, each R⁸ is independently selected from —(C₁-C₄)alkyl, -(5-or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), -halo, —N(R⁹)₂, —N(R⁹)S(═O)₂R², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, and —S(═O)₂R⁹. In another embodiment, each R⁸ isindependently selected from —(C₁-C₄)alkyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), -halo, —N(R⁹)₂, —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —C(═O)R⁹,—C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, and —S(═O)₂R⁹. In anotherembodiment, each R⁸ is independently selected from —(C₁-C₄)alkyl,—(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —C(halo)₃,—CH(halo)₂, —CH₂(halo), -halo, —N(R⁹)₂, —C(═O)N(T¹)(T²), and —C(═O)OR⁹.

In another embodiment, each R⁹ is independently —H, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₃-C₈)cycloalkyl, -phenyl, -benzyl, -(3- to7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo). In anotherembodiment, each R⁹ is independently —H, —(C₁-C₆)alkyl,—(C₃-C₈)cycloalkyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo). In another embodiment, each R⁹ isindependently —H, —(C₁-C₆)alkyl, —C(halo)₃, —CH(halo)₂, or —CH₂(halo).In another embodiment, each R⁹ is independently —H or —(C₁-C₃)alkyl.

In another embodiment, each T¹ and T² is independently —H or—(C₁-C₃)alkyl which is unsubstituted or substituted with anindependently selected R⁵ group. In another embodiment, each T¹ and T²is independently —H or —(C₁-C₃)alkyl which is unsubstituted. In anotherembodiment, each T¹ and T² is independently —H or —CH₃. In anotherembodiment, each T³ is independently —H or —(C₁-C₃)alkyl which isunsubstituted or substituted with an independently selected R⁵ group. Inanother embodiment, each T³ is independently —H or —(C₁-C₃)alkyl whichis unsubstituted. In another embodiment, each T³ is independently —H or—CH₃.

In another embodiment, each R⁵ is independently selected from—(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, -halo, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —S(═O)R⁹, and —S(═O)₂R⁹. In anotherembodiment, each R⁵ is independently selected from —(C₁-C₄)alkyl,—(C₂-C₆)alkenyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), ═O, ═S, -halo, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)OR⁹,—OC(═O)R⁹, —S(═O)R⁹, and —S(═O)₂R⁹. In another embodiment, each R⁵ isindependently selected from —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), -halo, —CH═N(R), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)₂R¹²,—N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, and—S(═O)₂R⁹. In another embodiment, each R⁵ is independently selected from—(C₁-C₄)alkyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), -halo, —N(R⁹)₂, —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, and —S(═O)₂R⁹. Inanother embodiment, each R⁵ is independently selected from—(C₁-C₄)alkyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), -halo, —N(R⁹)₂, —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —C(═O)R⁹,—C(═O)OR⁹, —OC(═O)R⁹, and —S(═O)₂R⁹. In another embodiment, each R⁵ isindependently selected from —(C₁-C₄)alkyl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo),-halo, —N(R⁹)₂, and —C(═O)OR⁹.

In another embodiment, R¹¹ is —H or —(C₁-C₄)alkyl which is unsubstitutedor substituted with —OH, —(C₁-C₄)alkoxy, or —N(R⁶)₂. In anotherembodiment, R¹¹ is —H. In another embodiment, R¹¹ is not —C(═O)OH.

In another embodiment, h is 0. In another embodiment, h is 1. In anotherembodiment, h is 1 and R¹³ is absent. In another embodiment, h is 0 andR¹¹ is —H. In another embodiment, h is 1 and R¹¹ is —H. In anotherembodiment, h is 0 or 1 and Z is —(C₁-C₁₀)alkyl unsubstituted by R¹³,i.e., Z is —[(C₁-C₁₀)alkyl]_(h).

In another embodiment, h is 1 and Z is —(C₁-C₃)alkyl optionallysubstituted by R¹³. In another embodiment, h is 1, R¹³ is absent, and Zis —CH₂—. In another embodiment, h is 1, R¹³ is absent, and Z is—CH₂—CH₂—. In another embodiment, h is 1, R¹³ is absent and Z is—CH₂—CH₂—CH₂—. In another embodiment, h is 1, Z is —(C₁-C₃)alkyl-, R¹ isphenyl, and the Z group (i.e., —(C₁-C₃)alkyl-) is substituted by R¹³. Inanother embodiment, h is 1, Z is a —(C₁-C₃)alkyl-, R¹ isoptionally-substituted phenyl, and the Z group is substituted by R¹³which is optionally-substituted phenyl. In another embodiment, h is 1, Zis a —(C₁-C₃)alkyl-, R¹ is unsubstituted phenyl, and the Z group issubstituted by R¹³ which is unsubstituted phenyl. In another embodiment,h is 1, Z is a —(C₁-C₃)alkyl-, and the Z group is substituted by R¹³which is —CF₃. In another embodiment, h is 1 and Z—R¹³ is—CH₂—CH(CF₃)—CH₂—.

In another embodiment, R¹ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,—(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)Cycloalkenyl,—(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with 1, 2, 3, or 4independently selected R⁸ groups.

In another embodiment, Z is —(C₂-C₁₀)alkenyl-. In another embodiment, Zis —(C₂-C₆)alkenyl-. In another embodiment, Z is —CH₂—CH═CH—. In anotherembodiment, Z is —CH₂—CH═CH—CH₂—. In another embodiment, Z is a—(C₃)alkenyl-. In another embodiment, Z is n-prop-1,3-diyl and R¹ is anoptionally substituted —(C₆-C₁₄)bicycloalkyl or optionally substituted—(C₈-C₂₀)tricycloalkyl. In another embodiment, Z—R¹ is —CH₂—CH═R¹. Inanother embodiment, Z—R¹ is —CH₂—CH₂—CH═R¹ or —CH(CH₃)—CH═R¹ where R¹ is—(C₆-C₁₄)bicycloalkyl or -(C₈-C₂₀)tricycloalkyl, each of which isoptionally substituted. In another embodiment, h is 1, and Z—R¹ is

In another embodiment, Y is O. In another embodiment, Y is S.

In another embodiment, Z is —CH₂—NH—C(═O)—. In another embodiment, Z is—CH₂—CH₂—NH—C(═O)—. In another embodiment, Z is —CH₂—NH—C(═S)—. Inanother embodiment, Z is —CH₂—CH₂—NH—C(═S)—. In another embodiment, Z is—CH₂—N(CH₃)—C(═O)—. In another embodiment, Z is —CH₂—CH₂—N(CH₃)—C(═O)—.In another embodiment, Z is —CH₂—N(CH₃)—C(═S)—. In another embodiment, Zis —CH₂—CH₂—N(CH₃)—C(═S)—.

In another embodiment, R¹ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,        —(C₃-C₁₄)cycloalkyl, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁷ groups.

In another embodiment, R¹ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁷ groups.

In another embodiment, R¹ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,        —(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl,        —(C₅-C₁₄)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,        —(C₈-C₂₀)tricycloalkenyl, and -(3- to 7-membered)heterocycle,        each of which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups.

In another embodiment, m is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In anotherembodiment, m is 2, 3, 4, 5, 6, 7, or 8. In another embodiment, m is 2,3, 4, 5, 6, or 7. In another embodiment, m is 2, 3, 4, 5, or 6. Inanother embodiment, m is 2, 3, 4, or 5. In another embodiment, m is 2.In another embodiment, m is 3. In another embodiment, m is 4. In anotherembodiment, m is 5. In another embodiment, m is 6. In anotherembodiment, m is 7.

In another embodiment, n is 2, 3, 4, 5, 6, 7, or 8. In anotherembodiment, n is 2, 3, 4, 5, 6, or 7. In another embodiment, n is 2, 3,4, 5, or 6. In another embodiment, n is 2, 3, 4, or 5. In anotherembodiment, n is 2. In another embodiment, n is 3. In anotherembodiment, n is 4. In another embodiment, n is 5. In anotherembodiment, n is 6. In another embodiment, n is 7.

In another embodiment, m is 1, 2, 3, 4, 5, 6, 7, 8, or 9 and n is 2, 3,4, 5, 6, 7, or 8. In another embodiment, m is 2, 3, 4, 5, 6, 7, or 8 andn is 2, 3, 4, 5, 6, 7, or 8. In another embodiment, m is 2, 3, 4, 5, 6,or 7 and n is 2, 3, 4, 5, 6, or 7. In another embodiment, m is 2, 3, 4,5, or 6 and n is 2, 3, 4, 5, or 6. In another embodiment, m is 2, 3, 4,or 5 and n is 2, 3, 4, or 5. In another embodiment, m=n. In anotherembodiment, m and n are each 2. In another embodiment, m and n are each3. In another embodiment, m and n are each 4. In another embodiment, mand n are each 5. In another embodiment, m and n are each 6. In anotherembodiment, m and n are each 7.

In another embodiment, e is 0 and f is 0. In another embodiment, e is 0and f is 1. In another embodiment, e is 1 and f is 0. In anotherembodiment, e is 1 and f is 1. In another embodiment, e is 1 and f is 2.In another embodiment, e is 2 and f is 1. In another embodiment, e is 2and f is 2.

In another embodiment, p is 0, 1, 2, or 3. In another embodiment, p is0, 1, or 2. In another embodiment, p is 1 or 2. In another embodiment, pis 2. In another embodiment, p is 1. In another embodiment, p is 0.

In another embodiment, R¹ is optionally substituted cyclooctyl. Inanother embodiment, R¹ is optionally substituted cyclooctenyl. Inanother embodiment, R¹ is optionally substituted anthryl.

In another embodiment, h is 0 and R¹ is optionally substitutedcyclooctyl. In another embodiment, h is 0 and R¹ is optionallysubstituted cycloundecyl. In another embodiment, h is 0 and R¹ isoptionally substituted cyclooctenyl. In another embodiment, h is 0 andR¹ is optionally substituted anthryl. In another embodiment, h is 0 andR¹ is optionally substituted —(C₆-C₁₄)bicycloalkyl. In anotherembodiment, h is 0 and R¹ is optionally substituted bicyclo[3.3.1]nonyl.In another embodiment, h is 0 and R¹ is optionally substitutedbicyclo[2.2.1.]hepyl. In another embodiment, h is 0 and R¹ is optionallysubstituted -(C₈-C₂₀)tricycloalkyl. In another embodiment, h is 0 and R¹is optionally substituted adamantyl. In another embodiment, h is 0 andR¹ is optionally substituted noradamantyl.

In another embodiment, —Z—R¹ is:

where each R^(z) is independently —H, —(C₁-C₄)alkyl, —OH, or —CN andpreferably each R^(z) is independently —H, —CH₃, or —CH₂CH₃. In anotherembodiment, —Z—R¹ is:

In another embodiment, —Z—R¹ is:

In another embodiment, —Z—R¹ is:

In another embodiment, —Z—R¹ is:

where R^(z) is —H, —CH₃, or —CH₂CH₃.

In another embodiment, Y₁ is O, A and B are each H, and a is 0 or 1. Inanother embodiment, Y₁ is S, A and B are each H, and a is 0 or 1. Inanother embodiment, Y₁ is O, A and B are each H, and a is 0. In anotherembodiment, Y₁ is S, A and B are each H, and a is 0. In anotherembodiment, Y₁ is O, A and B are each H, and a is 1. In anotherembodiment, Y₁ is S, A and B are each H, and a is 1.

In another embodiment, Y₁ is O, A and B are each H, h is 0, and a is 0or 1. In another embodiment, Y₁ is S, A and B are each H, h is 0, and ais 0 or 1. In another embodiment, Y₁ is O, A and B are each H, h is 0,and a is 0. In another embodiment, Y₁ is S, A and B are each H, h is 0,and a is 0. In another embodiment, Y₁ is O, A and B are each H, h is 0,and a is 1. In another embodiment, Y₁ is S, A and B are each H, h is 0,and a is 1. In another embodiment, Y₁ is O, A and B are each H, h is 1,Z is (C₁-C₄)alkyl unsubstituted by R¹³, and a is 0 or 1. In anotherembodiment, Y₁ is S, A and B are each H, h is 1, Z is (C₁-C₄)alkylunsubstituted by R¹³, and a is 0 or 1. In another embodiment, Y₁ is O, Aand B are each H, h is 1, Z is (C₁-C₄)alkyl unsubstituted by R¹³, and ais 0. In another embodiment, Y₁ is S, A and B are each H, h is 1, Z is(C₁-C₄)alkyl unsubstituted by R¹³, and a is 0. In another embodiment, Y₁is O, A and B are each H, h is 1, Z is (C₁-C₄)alkyl unsubstituted byR¹³, and a is 1. In another embodiment, Y₁ is S, A and B are each H, his 1, Z is (C₁-C₄)alkyl unsubstituted by R¹³, and a is 1.

In another embodiment, A and B are independently selected from:

-   -   (a) —H, —CN, —C(═O)OT³, and —C(═O)N(T¹)(T²); and    -   (b) —(C₃-C₁₂)cycloalkyl, —(C₃-C₁₂)cycloalkoxy, —(C₁-C₆)alkyl,        —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —N(R⁶)₂, ═NR⁶,        —C(═O)OT³, —C(═O)N(R⁶)₂, —N(R⁶)C(═O)R⁹, and -(5- or        6-membered)heterocycle, or 1, 2, or 3 independently selected        -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7 or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 6-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge.

In another embodiment, A and B are each independently —H or—(C₁-C₆)alkyl. In another embodiment, A is —(C₁-C₆)alkyl. In anotherembodiment, B is —(C₁-C₆)alkyl. In another embodiment, A and B are eachindependently —(C₁-C₆)alkyl. In another embodiment, A is —(C₁-C₆)alkyland B is H. In another embodiment, A is —H and B is —(C₁-C₆)alkyl. Inanother embodiment, A and B are each independently —H or —CH₃. Inanother embodiment, A is —CH₃. In another embodiment, B is —CH₃. Inanother embodiment, A and B are each —CH₃. In another embodiment, A is—CH₃ and B is H. In another embodiment, A is —H and B is —CH₃. Inanother embodiment, A is H. In another embodiment, B is H. In anotherembodiment, A and B are each H.

In another embodiment, A-B together form a (C₂)bridge which bridge issubstituted or unsubstituted. In another embodiment, A-B together form a(C₂)bridge which bridge is unsubstituted. In another embodiment, A-Btogether form a (C₂)bridge which bridge is substituted by one or twomethyl groups. In another embodiment, A-B together form a (C₃)bridgewhich bridge is substituted or unsubstituted. In another embodiment, A-Btogether form a (C₃)bridge which bridge is unsubstituted. In anotherembodiment, A-B together form a (C₃)bridge which bridge is substitutedby one or two methyl groups. In another embodiment, A-B together form a(C₄)bridge which bridge is substituted or unsubstituted. In anotherembodiment, A-B together form a (C₄)bridge which bridge isunsubstituted. In another embodiment, A-B together form a (C₄)bridgewhich bridge is substituted by one or two methyl groups. In anotherembodiment, A-B together form a (C₅)bridge which bridge is substitutedor unsubstituted. In another embodiment, A-B together form a (C₅)bridgewhich bridge is unsubstituted. In another embodiment, A-B together forma (C₅)bridge which bridge is substituted by one or two methyl groups. Inanother embodiment, A-B together form a (C₆)bridge which bridge issubstituted or unsubstituted. In another embodiment, A-B together form a(C₆)bridge which bridge is unsubstituted. In another embodiment, A-Btogether form a (C₆)bridge which bridge is substituted by one or twomethyl groups.

In another embodiment, A-B together form a (C₂)bridge which bridge is—HC═CH— and is substituted or unsubstituted. In another embodiment, A-Btogether form a (C₂)bridge which bridge is —HC═CH— and is unsubstituted.In another embodiment, A-B together form a (C₂)bridge which is —HC═CH—and is substituted by one or two methyl groups. In another embodiment,A-B together form a (C₃)bridge which is —CH₂—HC═CH— or —HC═CH—CH₂— andis substituted or unsubstituted. In another embodiment, A-B togetherform a (C₃)bridge which is —CH₂—HC═CH— or —HC═CH—CH₂— and isunsubstituted. In another embodiment, A-B together form a (C₃)bridgewhich is —CH₂—HC═CH— or —HC═CH—CH₂— and is substituted by one or twomethyl groups. In another embodiment, A-B together form a (C₄)bridgewhich is —CH₂—CH₂—HC═CH—, —CH₂—HC═CH—CH₂—, or —HC═CH—CH₂—CH₂— and issubstituted or unsubstituted. In another embodiment, A-B together form a(C₄)bridge which is —CH₂—CH₂—HC═CH—, —CH₂—HC═CH—CH₂—, or —HC═CH—CH₂—CH₂—and is unsubstituted. In another embodiment, A-B together form a(C₄)bridge which is —CH₂—CH₂—HC═CH—, —CH₂—HC═CH—CH₂—, or —HC═CH—CH₂—CH₂—and is substituted by one or two methyl groups.

In another embodiment, A-B together form a (C₂)bridge which is—CH₂—O—CH₂— and is substituted or unsubstituted. In another embodiment,A-B together form a (C₂)bridge which is —CH₂—O—CH₂— and isunsubstituted. In another embodiment, A-B together form a (C₂)bridgewhich is —CH₂—O—CH₂— and is substituted by one or two methyl groups. Inanother embodiment, A-B together form a (C₃)bridge which is—CH₂—O—CH₂—CH₂— or —CH₂—CH₂—O—CH₂— and is substituted or unsubstituted.In another embodiment, A-B together form a (C₃)bridge which is—CH₂—O—CH₂—CH₂— or —CH₂—CH₂—O—CH₂— and is unsubstituted. In anotherembodiment, A-B together form a (C₃)bridge which is —CH₂—O—CH₂—CH₂— or—CH₂—CH₂—O—CH₂— and is substituted by one or two methyl groups. Inanother embodiment, A-B together form a (C₄)bridge which is—CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, or —CH₂—CH₂—CH₂—O—CH₂— and issubstituted or unsubstituted. In another embodiment, A-B together form a(C₄)bridge which is —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, or—CH₂—CH₂—CH₂—O—CH₂— and is unsubstituted. In another embodiment, A-Btogether form a (C₄)bridge which is —CH₂—O—CH₂—CH₂—CH₂—,—CH₂—CH₂—O—CH₂—CH₂—, or —CH₂—CH₂—CH₂—O—CH₂— and is substituted by one ortwo methyl groups.

In another embodiment, A and B together form a bridge such that thebridged-piperidine is:

wherein each R^(d) is independently —H, —(C₁-C₄)alkyl, -halo, or—C(halo)₃. In another embodiment, A and B together form a bridge suchthat the bridged-piperidine is:

In another embodiment, A and B together form a bridge such that thebridged-piperidine is:

In another embodiment, the A-B bridge of the bridged-piperidine is inthe endo-configuration with respect to the 6-membered,nitrogen-containing ring that is fused to the Q_(a) ring.

In another embodiment, the pharmaceutically acceptable salt or solvateof a compounds of Formula (I) is a pharmaceutically acceptable salt. Inanother embodiment, the pharmaceutically acceptable salt is ahydrochloride salt. In another embodiment, the pharmaceuticallyacceptable salt is a sodium salt. In another embodiment, thepharmaceutically acceptable salt is a potassium salt. In anotherembodiment, the pharmaceutically acceptable salt is apara-toluenesulfonic acid salt.

In other embodiments, the Substituted Benzimidazole-Type PiperidineCompound of Formula (I) has one of the formulae of Table 1.

TABLE 1 Formula Compound IAA

IAB

IAC

IAD

IAD₁ ^(†)

IAD₂ ^(‡)

IAE

IAE₁ ^(†)

IAE₂ ^(‡)

IAF

IAF₁ ^(†)

IAF₂ ^(‡)

IAG

IAG₁ ^(†)

IAG₂ ^(‡)

IAH

IAH₁ ^(†)

IAH₂ ^(‡)

IAJ

IAJ₁ ^(†)

IAJ₂ ^(‡)

IAK

IAK₁ ^(†)

IAK₂ ^(‡)

IAL

IAL₁ ^(†)

IAL₂ ^(‡)

IAM

IAM₁ ^(†)

IAM₂ ^(‡)

^(†)indicates the 5-membered, nitrogen-containing ring that is fused tothe benzo or pyridino is in the endo-configuration with respect to thealkyl or —CH₂—O—CH₂— bridge. ^(‡)indicates the 5-membered,nitrogen-containing ring that is fused to the benzo or pyridino is inthe exo-configuration with respect to the alkyl or —CH₂—O—CH₂— bridge.where R¹, R², R¹¹, U, Z, and a are as defined above for the SubstitutedBenzimidazole-Type Piperidine Compounds of Formula (I) and —W— is asingle bond, —CH₂—, —NH—, —O—, —CH₂—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, —CH₂—(C₂-C₃)alkenylene-,—NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,—O—(C₁-C₃)alkylene-N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—, —CH₂—O—, or—CH₂—O—(C₁-C₃)alkylene-.

4.2 SUBSTITUTED BENZIMIDAZOLE-TYPE PIPERIDINE COMPOUNDS OF FORMULA (IA)

As stated above, the disclosure encompasses SubstitutedBenzimidazole-Type Piperidine Compounds of Formula (IA):

or a pharmaceutically acceptable derivative thereof where each dashedline, Q_(a), Q_(x), R¹, R², R³, R¹⁰, A, B, U¹, U², Z, a, s, and t aredefined above for the Substituted Benzimidazole-Type PiperidineCompounds of Formula (IA).

In one embodiment, the compound of formula (IA) is a compound of formula(IA′):

or a pharmaceutically acceptable salt or solvate thereof where R¹, R²,R¹⁰, Q_(a), Q_(x), U¹, U², A, B, Z, a, s, and t are as defined for thecompounds of formula (IA).

In another embodiment, the compound of formula (IA) is a compound offormula (IA″):

or a pharmaceutically acceptable salt or solvate thereof where R¹, R²,R³, R¹⁰, Q_(a), Q_(x), U¹, U², A, B, Z, a, s, and t are as defined forthe compounds of formula (IA).

4.2a Substituted Benzimidazole-Type Piperidine Compounds of Formulae(IA), (IA′), and (IA″)

In one embodiment, t is 1 and the Q_(x) ring is selected from:

In another embodiment, t is 1, 2, or 3 and the Q_(x) ring is selectedfrom:

In another embodiment, t is 1 and the Q_(x) ring is selected from:

In another embodiment, t is 0, 1, 2, or 3 and the Q_(x) ring is selectedfrom:

In another embodiment, t is 0 and the Q_(x) ring is selected from:

In another embodiment, t is 0 and the Q_(x) ring is selected from:

In another embodiment, t is 1 and the Q_(x) ring is selected from:

In another embodiment, t is 1 and the Q_(x) ring is selected from:

In another embodiment, s is 0, t is 1, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 0, t is 1, 2, or 3, and the Q_(x) ring isselected from:

In another embodiment, s is 0, t is 1, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 0, t is 0, 1, 2, or 3, and the Q_(x) ring isselected from:

In another embodiment, s is 0, t is 0, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 0, t is 0, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 0, t is 1, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 0, t is 1, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 1, t is 1, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 1, t is 1, 2, or 3, and the Q_(x) ring isselected from:

In another embodiment, s is 1, t is 1, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 1, t is 0, 1, 2, or 3, and the Q_(x) ring isselected from:

In another embodiment, s is 1, t is 0, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 1, t is 0, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 1, t is 1, and the Q_(x) ring is selectedfrom:

In another embodiment, s is 1, t is 1, and the Q_(x) ring is selectedfrom:

In another embodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₆)alkyl, CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, R⁴ is CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, R⁴ isCH₂CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₆)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₆)alkyl, CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₆)alkyl, C(═O)O—(C₁-C₆)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, R⁴ isCH₂CH₂C(═O)O—(C₁-C₆)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₆)alkyl,CH₂C(═O)OH, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment,R⁴ is CH₂CH₂C(═O)O—(C₁-C₆)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₆)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₆)alkyl, CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, or C(═O)OH.

In another embodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₆)alkyl or CH₂CH₂C(═O)OH.In another embodiment, R⁴ is CH₂CH₂C(═O)OH or CH₂C(═O)O—(C₁-C₆)alkyl. Inanother embodiment, R⁴ is CH₂C(═O)O—(C₁-C₆)alkyl or CH₂C(═O)OH. Inanother embodiment, R⁴ is CH₂C(═O)OH or C(═O)O—(C₁-C₆)alkyl. In anotherembodiment, R⁴ is C(═O)O—(C₁-C₆)alkyl or C(═O)OH. In another embodiment,R⁴ is CH₂CH₂C(═O)O—(C₁-C₆)alkyl or CH₂C(═O)NH(C₁-C₆)alkyl.

In another embodiment, R⁴ is CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. Inanother embodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ isCH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ isCH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)OH, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment,R⁴ is CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, or C(═O)OH.

In another embodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₄)alkyl or CH₂CH₂C(═O)OH.In another embodiment, R⁴ is CH₂CH₂C(═O)OH or CH₂C(═O)O—(C₁-C₄)alkyl. Inanother embodiment, R⁴ is CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)OH. Inanother embodiment, R⁴ is CH₂C(═O)OH or C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, R⁴ is C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In another embodiment,R⁴ is CH₂CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₆)alkyl. In anotherembodiment, R⁴ is CH₂CH₂C(═O)OH. In another embodiment, R⁴ isCH₂C(═O)O—(C₁-C₆)alkyl. In another embodiment, R⁴ is CH₂C(═O)OH. Inanother embodiment, R⁴ is C(═O)O—(C₁-C₆)alkyl. In another embodiment, R⁴is C(═O)OH. In another embodiment, R⁴ is CH₂C(═O)NH(C₁-C₆)alkyl. Inanother embodiment, R⁴ is CH₂CH₂C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, R⁴ is CH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ isC(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ isCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H. In anotherembodiment, R⁴ is absent.

In another embodiment, R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, R¹⁰ is CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, R¹⁰ isCH₂C(═O)O—(C₁-C₆)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, or CH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment,R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, orC(═O)OH.

In another embodiment, R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, orC(═O)O—(C₁-C₆)alkyl. In another embodiment, R¹⁰ is CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, or C(═O)OH. In another embodiment, R¹⁰ is C(═O)OHor CH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, R¹⁰ isCH₂C(═O)O—(C₁-C₆)alkyl or CH₂C(═O)NH(C₁-C₆)alkyl.

In another embodiment, R¹⁰ is CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R¹⁰ isCH₂C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, R¹⁰ is CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment,R¹⁰ is CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, orC(═O)OH.

In another embodiment, R¹⁰ is CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl. In another embodiment, R¹⁰ is CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In another embodiment, R¹⁰ is C(═O)OH orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R¹⁰ isCH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl. In anotherembodiment, R¹⁰ is CH₂C(═O)OH. In another embodiment, R¹⁰ isC(═O)O—(C₁-C₆)alkyl. In another embodiment, R¹⁰ is C(═O)OH. In anotherembodiment, R¹⁰ is CH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, R¹⁰ isCH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, R¹⁰ isC(═O)O—(C₁-C₄)alkyl. In another embodiment, R¹⁰ isCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R¹⁰ is CH₃ or CH₂CH₃. Inanother embodiment, R¹⁰ is CH₃. In another embodiment, R¹⁰ is CH₂CH₃.

In another embodiment, s is 0 or 1. In another embodiment, s is 1 or 2.In another embodiment, s is 0. In another embodiment, s is 1. In anotherembodiment, s is 2.

In another embodiment, s is 1 and R¹⁰ is CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, CH₂C(═O)O—(C₁-C₆)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl,or CH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 2 and each R¹⁰is, independently, CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, or C(═O)OH.

In another embodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, or C(═O)O—(C₁-C₆)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, or C(═O)OH. In another embodiment, s is 2 and eachR¹⁰ is, independently, C(═O)OH or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₆)alkyl or CH₂C(═O)NH(C₁-C₆)alkyl.

In another embodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. Inanother embodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl,or C(═O)OH.

In another embodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In another embodiment, s is 2 and eachR¹⁰ is, independently, C(═O)OH or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₆)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, CH₂C(═O)OH. In another embodiment, s is 2 and each R¹⁰is, independently, C(═O)O—(C₁-C₆)alkyl. In another embodiment, s is 2and each R¹⁰ is, independently, C(═O)OH. In another embodiment, s is 2and each R¹¹ is, independently, CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, C(═O)O—(C₁-C₄)alkyl.

In another embodiment, R³ is absent. In another embodiment, R³ is H,CH₂C(═O)OH, CH₂C(═O)OCH₃, CH₂C(═O)NH₂, CH₂C(═O)NHCH₃, orCH₂C(═O)NH(CH₃)₂. In another embodiment, R³ is H, CH₂C(═O)OH,CH₂C(═O)OCH₃, CH₂C(═O)NH₂, or CH₂C(═O)NHCH₃. In another embodiment, R³is H, CH₂C(═O)OH, or CH₂C(═O)NH₂. In another embodiment, R³ is H orCH₂C(═O)OH. In another embodiment, R³ is H or CH₂C(═O)NH₂. In anotherembodiment, R³ is H. In another embodiment, R³ is CH₂C(═O)OH. In anotherembodiment, R³ is CH₂C(═O)NH₂.

Each and every embodiment set forth in Section 4.1 relating to thepiperidine ring and the A, B, Z, and R¹ substituents thereto, and to theQ_(a), R², R³, and a variable groups referenced therein also relate tothe Substituted Benzimidazole-Type Piperidine Compounds in this section;therefore, those embodiments are not repeated here but are insteadincorporated by reference in their entirety.

4.2b Substituted Benzimidazole-Type Piperidine Compounds of Formulae(IA), (IA′), and (IA″)

In another embodiment, t is 1, 2, or 3, s is 0 or 1, and the Q_(x) ringis selected from:

In another embodiment, t is 1, s is 0 or 1, and the Q_(x) ring isselected from:

In another embodiment, t is 0, s is 0 or 1, and the Q_(x) ring isselected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrimidyl, and pyrazyl.

In another embodiment, t is 0, s is 0 or 1, and the Q_(x) ring isselected from pyrazolyl, imidazolyl, isoxazolyl, and pyrazyl.

In another embodiment, t is 0, s is 0 or 1, and the Q_(x) ring isselected from pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl,pyridazyl, and pyrimidyl.

In another embodiment, t is 0, s is 0 or 1, and the Q_(x) ring isselected from:

In another embodiment, t is 0, s is 0 or 1, and the Q_(x) ring isselected from:

In another embodiment, t is 0, s is 0 or 1, and the Q_(x) ring isselected from:

In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,CH₂C(═O)NH(C₁-C₄)alkyl, or CH₂C(═O)N[(C₁-C₄)alkyl]₂. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl,C(═O)OH, CH₂C(═O)NH(C₁-C₄)alkyl, or CH₂C(═O)N[(C₁-C₄)alkyl]₂. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, C(═O)OH, CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,CH₂C(═O)NH(C₁-C₄)alkyl, or CH₂C(═O)N[(C₁-C₄)alkyl]₂. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,C(═O)O—(C₁-C₄)alkyl, C(═O)OH, CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)OH,CH₂C(═O)NH(C₁-C₄)alkyl, or CH₂C(═O)N[(C₁-C₄)alkyl]₂. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl,or C(═O)OH.

In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl or CH₂CH₂C(═O)OH.In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)OH or CH₂C(═O)O—(C₁-C₄)alkyl. Inanother embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)OH. Inanother embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂C(═O)OH or C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)NH(C₁-C₄)alkyl, or CH₂C(═O)N[(C₁-C₄)alkyl]₂.

In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. Inanother embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl,or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl,or C(═O)OH.

In another embodiment, R⁴ is H, 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, or CH₂CH₂C(═O)OH. In another embodiment, R⁴is H, 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)OH, orCH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1-methyl-1H-imidazole), CH₂C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)OH. Inanother embodiment, R⁴ is H, 2-(1-methyl-1H-imidazole), CH₂C(═O)OH, orC(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1-methyl-1H-imidazole), C(═O)O—(C₁-C₄)alkyl, or C(═O)OH. In anotherembodiment, R⁴ is H, 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, R⁴ is H or CH₂CH₂C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H or CH₂CH₂C(═O)OH. In another embodiment, R⁴ is H orCH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ is H or CH₂C(═O)OH. Inanother embodiment, R⁴ is H or C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H or C(═O)OH. In another embodiment, R⁴ is H,2-(1-methyl-1H-imidazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H orCH₂CH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ is H orCH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ is H orC(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ is H orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), or 2-(1-methyl-1H-imidazole). In another embodiment,R⁴ is H or 2-(1H-imidazole). In another embodiment, R⁴ is H or2-(1-methyl-1H-imidazole). In another embodiment, R⁴ is2-(1H-imidazole). In another embodiment, R⁴ is2-(1-methyl-1H-imidazole).

In another embodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl,C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 1 andR¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, or C(═O)OH.

In another embodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl,CH₂C(═O)OH, or C(═O)O—(C₁-C₆)alkyl. In another embodiment, s is 1 andR¹⁰ is CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, or C(═O)OH. In anotherembodiment, s is 1 and R¹⁰ is C(═O)OH or CH₂C(═O)NH(C₁-C₆)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl orCH₂C(═O)NH(C₁-C₆)alkyl.

In another embodiment, s is 1 and R¹⁰ is CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ isCH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, is 1 and R¹⁰ isCH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, or C(═O)OH.

In another embodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₄)alkyl orCH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰is CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In another embodiment, sis 1 and R¹⁰ is C(═O)OH or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₄)alkyl orCH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₆)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₂C(═O)OH. In another embodiment,s is 1 and R¹⁰ is C(═O)O—(C₁-C₆)alkyl. In another embodiment, s is 1 andR¹⁰ is C(═O)OH. In another embodiment, s is 1 and R¹⁰ isCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 1 and R¹⁰ isCH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ isC(═O)O—(C₁-C₄)alkyl.

In another embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ is CH₃,CH₂CH₃, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ is CH₃,CH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ is CH₃,CH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, orC(═O)OH.

In another embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In another embodiment, s is 1 and R¹⁰ isCH₃, CH₂CH₃, C(═O)OH or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, sis 1 and R¹⁰ is CH₃, CH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl orCH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl,C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 andR¹⁰ is CH₃, CH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, sis 1 and R¹⁰ is CH₃, CH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, or C(═O)OH.

In another embodiment, s is 1 and R¹⁰ is CH₃, CH₂C(═O)O—(C₁-C₄)alkyl orCH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰is CH₃, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In anotherembodiment, s is 1 and R¹⁰ is CH₃, C(═O)OH or CH₂C(═O)NH(C₁-C₄)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₃, CH₂C(═O)O—(C₁-C₄)alkyl orCH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 1 and R¹⁰ is CH₂C(═O)O—(C₁-C₄)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₂C(═O)OH. In another embodiment,s is 1 and R¹⁰ is C(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 1 andR¹⁰ is C(═O)OH. In another embodiment, s is 1 and R¹⁰ isCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ isCH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ isC(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ isCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ is CH₃ orCH₂CH₃. In another embodiment, s is 1 and R¹⁰ is CH₃. In anotherembodiment, s is 1 and R¹⁰ is CH₂CH₃.

In another embodiment, R¹ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₂-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, -(3- to        5-membered)heterocycle, and -(7-membered)heterocycle, each of        which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups; and    -   (c)

-   -    and    -   (d) -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups.

In another embodiment, R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₂-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

and

(d) -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁷ groups wherein pis 0 or 1, optionally 0.

Each and every embodiment set forth in Sections 4.1 and 4.2a relating tothe piperidine ring and the A, B, Z, and R¹ substituents thereto, and tothe Q_(a), Q_(x), R², R³, R⁴, R¹⁰, a, s, and t variable groupsreferenced therein also relate to the Substituted Benzimidazole-TypePiperidine Compounds in this section; therefore, those embodiments arenot repeated here but are instead incorporated by reference in theirentirety.

4.2c Substituted Benzimidazole-Type Piperidine Compounds of Formula (IA)

Illustrative compounds of formula (IA) are listed below in Tables 2-16.

TABLE 2

(a)

(b)

(c)

(d)

(e)

(f)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) or R^(10a) R^(8a) y A A1 a, b, c, d, e, or f H H 1 A2a, b, c, d, e, or f C(═O)OH H 1 A3 a, b, c, d, e, or f C(═O)OCH₃ H 1 A4a, b, c, d, e, or f CH₂C(═O)OH H 1 A5 a, b, c, d, e, or f CH₂C(═O)OCH₃ H1 A6 a, b, c, d, e, or f CH₂CH₂C(═O)OH H 1 A7 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ H 1 A8 a, b, c, d, e, or f C(═O)NH₂ H 1 A9 a, b, c, d,e, or f C(═O)NHCH₃ H 1 A10 a, b, c, d, e, or f CH₂C(═O)NH₂ H 1 A11 a, b,c, d, e, or f CH₂C(═O)NHCH₃ H 1 A12 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H1 A13 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 1 A14 a, b, c, d, e, or f HCH₃ 1 A15 a, b, c, d, e, or f C(═O)OH CH₃ 1 A16 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 1 A17 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 1 A18 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 1 A19 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 1A20 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 1 A21 a, b, c, d, e, or fC(═O)NH₂ CH₃ 1 A22 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 1 A23 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 1 A24 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 1A25 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 1 A26 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 1 A27 a, b, c, d, e, or f H H 2 A28 a, b, c, d, e,or f C(═O)OH H 2 A29 a, b, c, d, e, or f C(═O)OCH₃ H 2 A30 a, b, c, d,e, or f CH₂C(═O)OH H 2 A31 a, b, c, d, e, or f CH₂C(═O)OCH₃ H 2 A32 a,b, c, d, e, or f CH₂CH₂C(═O)OH H 2 A33 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ H 2 A34 a, b, c, d, e, or f C(═O)NH₂ H 2 A35 a, b, c, d,e, or f C(═O)NHCH₃ H 2 A36 a, b, c, d, e, or f CH₂C(═O)NH₂ H 2 A37 a, b,c, d, e, or f CH₂C(═O)NHCH₃ H 2 A38 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H2 A39 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 2 A40 a, b, c, d, e, or f HCH₃ 2 A41 a, b, c, d, e, or f C(═O)OH CH₃ 2 A42 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 2 A43 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 2 A44 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 2 A45 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 2A46 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 2 A47 a, b, c, d, e, or fC(═O)NH₂ CH₃ 2 A48 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 2 A49 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 2 A50 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 2A51 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 2 A52 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 2 A53 a, b, c, d, e, or f H H 3 A54 a, b, c, d, e,or f C(═O)OH H 3 A55 a, b, c, d, e, or f C(═O)OCH₃ H 3 A56 a, b, c, d,e, or f CH₂C(═O)OH H 3 A57 a, b, c, d, e, or f CH₂C(═O)OCH₃ H 3 A58 a,b, c, d, e, or f CH₂CH₂C(═O)OH H 3 A59 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ H 3 A60 a, b, c, d, e, or f C(═O)NH₂ H 3 A61 a, b, c, d,e, or f C(═O)NHCH₃ H 3 A62 a, b, c, d, e, or f CH₂C(═O)NH₂ H 3 A63 a, b,c, d, e, or f CH₂C(═O)NHCH₃ H 3 A64 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H3 A65 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 3 A66 a, b, c, d, e, or f HCH₃ 3 A67 a, b, c, d, e, or f C(═O)OH CH₃ 3 A68 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 3 A69 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 3 A70 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 3 A71 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 3A72 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 3 A73 a, b, c, d, e, or fC(═O)NH₂ CH₃ 3 A74 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 3 A75 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 3 A76 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 3A77 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 3 A78 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atom thatis bonded to the 5-membered, nitrogen-containing ring that is fused tobenzo is in the (R)-conformation, (ii) indicates that Q_(x) ring carbonatom that is bonded to the 5-membered, nitrogen-containing ring that isfused to benzo is in the (S)-conformation.

TABLE 3

(a)

(b)

(c)

(d)

(e)

(f)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) or R^(10a) R^(8a) y B B1 a, b, c, d, e, or f H H 1 B2a, b, c, d, e, or f C(═O)OH H 1 B3 a, b, c, d, e, or f C(═O)OCH₃ H 1 B4a, b, c, d, e, or f CH₂C(═O)OH H 1 B5 a, b, c, d, e, or f CH₂C(═O)OCH₃ H1 B6 a, b, c, d, e, or f CH₂CH₂C(═O)OH H 1 B7 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ H 1 B8 a, b, c, d, e, or f C(═O)NH₂ H 1 B9 a, b, c, d,e, or f C(═O)NHCH₃ H 1 B10 a, b, c, d, e, or f CH₂C(═O)NH₂ H 1 B11 a, b,c, d, e, or f CH₂C(═O)NHCH₃ H 1 B12 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H1 B13 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 1 B14 a, b, c, d, e, or f HCH₃ 1 B15 a, b, c, d, e, or f C(═O)OH CH₃ 1 B16 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 1 B17 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 1 B18 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 1 B19 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 1B20 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 1 B21 a, b, c, d, e, or fC(═O)NH₂ CH₃ 1 B22 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 1 B23 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 1 B24 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 1B25 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 1 B26 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 1 B27 a, b, c, d, e, or f H H 2 B28 a, b, c, d, e,or f C(═O)OH H 2 B29 a, b, c, d, e, or f C(═O)OCH₃ H 2 B30 a, b, c, d,e, or f CH₂C(═O)OH H 2 B31 a, b, c, d, e, or f CH₂C(═O)OCH₃ H 2 B32 a,b, c, d, e, or f CH₂CH₂C(═O)OH H 2 B33 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ H 2 B34 a, b, c, d, e, or f C(═O)NH₂ H 2 B35 a, b, c, d,e, or f C(═O)NHCH₃ H 2 B36 a, b, c, d, e, or f CH₂C(═O)NH₂ H 2 B37 a, b,c, d, e, or f CH₂C(═O)NHCH₃ H 2 B38 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H2 B39 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 2 B40 a, b, c, d, e, or f HCH₃ 2 B41 a, b, c, d, e, or f C(═O)OH CH₃ 2 B42 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 2 B43 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 2 B44 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 2 B45 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 2B46 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 2 B47 a, b, c, d, e, or fC(═O)NH₂ CH₃ 2 B48 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 2 B49 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 2 B50 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 2B51 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 2 B52 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 2 B53 a, b, c, d, e, or f H H 3 B54 a, b, c, d, e,or f C(═O)OH H 3 B55 a, b, c, d, e, or f C(═O)OCH₃ H 3 B56 a, b, c, d,e, or f CH₂C(═O)OH H 3 B57 a, b, c, d, e, or f CH₂C(═O)OCH₃ H 3 B58 a,c, d, e, or f CH₂CH₂C(═O)OH H 3 B59 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃H 3 B60 a, b, c, d, e, or f C(═O)NH₂ H 3 B61 a, b, c, d, e, or fC(═O)NHCH₃ H 3 B62 a, c, d, e, or f CH₂C(═O)NH₂ H 3 B63 a, b, c, d, e,or f CH₂C(═O)NHCH₃ H 3 B64 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H 3 B65 a,b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 3 B66 a, b, c, d, e, or f H CH₃ 3B67 a, b, c, d, e, or f C(═O)OH CH₃ 3 B68 a, b, c, d, e, or f C(═O)OCH₃CH₃ 3 B69 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 3 B70 a, b, c, d, e, or fCH₂C(═O)OCH₃ CH₃ 3 B71 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 3 B72 a, b,c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 3 B73 a, b, c, d, e, or f C(═O)NH₂ CH₃3 B74 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 3 B75 a, b, c, d, e, or fCH₂C(═O)NH₂ CH₃ 3 B76 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 3 B77 a, b,c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 3 B78 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atom thatis bonded to the 5-membered, nitrogen-containing ring that is fused tobenzo is in the (R)-conformation, (ii) indicates that Q_(x) ring carbonatom that is bonded to the 5-membered, nitrogen-containing ring that isfused to benzo is in the (S)-conformation.

TABLE 4

(a)

(b)

(c)

(d)

(e)

(f)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) or R^(10a) R^(8a) y C C1 a, b, c, d, e, or f H H 1 C2a, b, c, d, e, or f C(═O)OH H 1 C3 a, b, c, d, e, or f C(═O)OCH₃ H 1 C4a, b, c, d, e, or f CH₂C(═O)OH H 1 C5 a, b, c, d, e, or f CH₂C(═O)OCH₃ H1 C6 a, b, c, d, e, or f CH₂CH₂C(═O)OH H 1 C7 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ H 1 C8 a, b, c, d, e, or f C(═O)NH₂ H 1 C9 a, b, c, d,e, or f C(═O)NHCH₃ H 1 C10 a, b, c, d, e, or f CH₂C(═O)NH₂ H 1 C11 a, b,c, d, e, or f CH₂C(═O)NHCH₃ H 1 C12 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H1 C13 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 1 C14 a, b, c, d, e, or f HCH₃ 1 C15 a, b, c, d, e, or f C(═O)OH CH₃ 1 C16 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 1 C17 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 1 C18 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 1 C19 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 1C20 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 1 C21 a, b, c, d, e, or fC(═O)NH₂ CH₃ 1 C22 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 1 C23 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 1 C24 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 1C25 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 1 C26 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 1 C27 a, b, c, d, e, or f H H 2 C28 a, b, c, d, e,or f C(═O)OH H 2 C29 a, b, c, d, e, or f C(═O)OCH₃ H 2 C30 a, b, c, d,e, or f CH₂C(═O)OH H 2 C31 a, b, c, d, e, or f CH₂C(═O)OCH₃ H 2 C32 a,b, c, d, e, or f CH₂CH₂C(═O)OH H 2 C33 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ H 2 C34 a, b, c, d, e, or f C(═O)NH₂ H 2 C35 a, b, c, d,e, or f C(═O)NHCH₃ H 2 C36 a, b, c, d, e, or f CH₂C(═O)NH₂ H 2 C37 a, b,c, d, e, or f CH₂C(═O)NHCH₃ H 2 C38 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H2 C39 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 2 C40 a, b, c, d, e, or f HCH₃ 2 C41 a, b, c, d, e, or f C(═O)OH CH₃ 2 C42 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 2 C43 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 2 C44 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 2 C45 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 2C46 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 2 C47 a, b, c, d, e, or fC(═O)NH₂ CH₃ 2 C48 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 2 C49 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 2 C50 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 2C51 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 2 C52 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 2 C53 a, b, c, d, e, or f H H 3 C54 a, b, c, d, e,or f C(═O)OH H 3 C55 a, b, c, d, e, or f C(═O)OCH₃ H 3 C56 a, b, c, d,e, or f CH₂C(═O)OH H 3 C57 a, b, c, d, e, or f CH₂C(═O)OCH₃ H 3 C58 a,b, c, d, e, or f CH₂CH₂C(═O)OH H 3 C59 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ H 3 C60 a, b, c, d, e, or f C(═O)NH₂ H 3 C61 a, b, c, d,e, or f C(═O)NHCH₃ H 3 C62 a, b, c, d, e, or f CH₂C(═O)NH₂ H 3 C63 a, b,c, d, e, or f CH₂C(═O)NHCH₃ H 3 C64 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ H3 C65 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ H 3 C66 a, b, c, d, e, or f HCH₃ 3 C67 a, b, c, d, e, or f C(═O)OH CH₃ 3 C68 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 3 C69 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 3 C70 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 3 C71 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 3C72 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 3 C73 a, b, c, d, e, or fC(═O)NH₂ CH₃ 3 C74 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 3 C75 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 3 C76 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 3C77 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 3 C78 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atom thatis bonded to the 5-membered, nitrogen-containing ring that is fused tobenzo is in the (R)-conformation, (ii) indicates that Q_(x) ring carbonatom that is bonded to the 5-membered, nitrogen-containing ring that isfused to benzo is in the (S)-conformation.

TABLE 5

(a)

(b)

(c)

(d)

(e)

(f)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) R^(8a) y D D1 c or f H H 1 D2 c or f C(═O)OH H 1 D3 cor f C(═O)OCH₃ H 1 D4 c or f CH₂C(═O)OH H 1 D5 c or f CH₂C(═O)OCH₃ H 1D6 c or f CH₂CH₂C(═O)OH H 1 D7 c or f CH₂CH₂C(═O)OCH₃ H 1 D8 c or fC(═O)NH₂ H 1 D9 c or f C(═O)NHCH₃ H 1 D10 c or f CH₂C(═O)NH₂ H 1 D11 cor f CH₂C(═O)NHCH₃ H 1 D12 c or f CH₂CH₂C(═O)NH₂ H 1 D13 c or fCH₂CH₂C(═O)NHCH₃ H 1 D14 a, b, c, d, e, or f H CH₃ 1 D15 a, b, c, d, e,or f C(═O)OH CH₃ 1 D16 a, b, c, d, e, or f C(═O)OCH₃ CH₃ 1 D17 a, b, c,d, e, or f CH₂C(═O)OH CH₃ 1 D18 a, b, c, d, e, or f CH₂C(═O)OCH₃ CH₃ 1D19 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 1 D20 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ CH₃ 1 D21 a, b, c, d, e, or f C(═O)NH₂ CH₃ 1 D22 a, b,c, d, e, or f C(═O)NHCH₃ CH₃ 1 D23 a, b, c, d, e, or f CH₂C(═O)NH₂ CH₃ 1D24 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 1 D25 a, b, c, d, e, or fCH₂CH₂C(═O)NH₂ CH₃ 1 D26 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ CH₃ 1 D27c or f H H 2 D28 c or f C(═O)OH H 2 D29 c or f C(═O)OCH₃ H 2 D30 c or fCH₂C(═O)OH H 2 D31 c or f CH₂C(═O)OCH₃ H 2 D32 c or f CH₂CH₂C(═O)OH H 2D33 c or f CH₂CH₂C(═O)OCH₃ H 2 D34 c or f C(═O)NH₂ H 2 D35 c or fC(═O)NHCH₃ H 2 D36 c or f CH₂C(═O)NH₂ H 2 D37 c or f CH₂C(═O)NHCH₃ H 2D38 c or f CH₂CH₂C(═O)NH₂ H 2 D39 c or f CH₂CH₂C(═O)NHCH₃ H 2 D40 a, b,c, d, e, or f H CH₃ 2 D41 a, b, c, d, e, or f C(═O)OH CH₃ 2 D42 a, b, c,d, e, or f C(═O)OCH₃ CH₃ 2 D43 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 2 D44a, b, c, d, e, or f CH₂C(═O)OCH₃ CH₃ 2 D45 a, b, c, d, e, or fCH₂CH₂C(═O)OH CH₃ 2 D46 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 2 D47 a,b, c, d, e, or f C(═O)NH₂ CH₃ 2 D48 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 2D49 a, b, c, d, e, or f CH₂C(═O)NH₂ CH₃ 2 D50 a, b, c, d, e, or fCH₂C(═O)NHCH₃ CH₃ 2 D51 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 2 D52 a,b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ CH₃ 2 D53 c or f H H 3 D54 c or fC(═O)OH H 3 D55 c or f C(═O)OCH₃ H 3 D56 c or f CH₂C(═O)OH H 3 D57 c orf CH₂C(═O)OCH₃ H 3 D58 c or f CH₂CH₂C(═O)OH H 3 D59 c or fCH₂CH₂C(═O)OCH₃ H 3 D60 c or f C(═O)NH₂ H 3 D61 c or f C(═O)NHCH₃ H 3D62 c or f CH₂C(═O)NH₂ H 3 D63 c or f CH₂C(═O)NHCH₃ H 3 D64 c or fCH₂CH₂C(═O)NH₂ H 3 D65 c or f CH₂CH₂C(═O)NHCH₃ H 3 D66 a, b, c, d, e, orf H CH₃ 3 D67 a, b, c, d, e, or f C(═O)OH CH₃ 3 D68 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 3 D69 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 3 D70 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 3 D71 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 3D72 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 3 D73 a, b, c, d, e, or fC(═O)NH₂ CH₃ 3 D74 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 3 D75 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 3 D76 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 3D77 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 3 D78 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atom thatis bonded to the 5-membered, nitrogen-containing ring that is fused tobenzo is in the (R)-conformation, (ii) indicates that Q_(x) ring carbonatom that is bonded to the 5-membered, nitrogen-containing ring that isfused to benzo is in the (S)-conformation.

TABLE 6

(a)

(b)

(c)

(d)

(e)

(f)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) R^(8a) y E E1 c or f H H 1 E2 c or f C(═O)OH H 1 E3 cor f C(═O)OCH₃ H 1 E4 c or f CH₂C(═O)OH H 1 E5 c or f CH₂C(═O)OCH₃ H 1E6 c or f CH₂CH₂C(═O)OH H 1 E7 c or f CH₂CH₂C(═O)OCH₃ H 1 E8 c or fC(═O)NH₂ H 1 E9 c or f C(═O)NHCH₃ H 1 E10 c or f CH₂C(═O)NH₂ H 1 E11 cor f CH₂C(═O)NHCH₃ H 1 E12 c or f CH₂CH₂C(═O)NH₂ H 1 E13 c or fCH₂CH₂C(═O)NHCH₃ H 1 E14 a, b, c, d, e, or f H CH₃ 1 E15 a, b, c, d, e,or f C(═O)OH CH₃ 1 E16 a, b, c, d, e, or f C(═O)OCH₃ CH₃ 1 E17 a, b, c,d, e, or f CH₂C(═O)OH CH₃ 1 E18 a, b, c, d, e, or f CH₂C(═O)OCH₃ CH₃ 1E19 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 1 E20 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ CH₃ 1 E21 a, b, c, d, e, or f C(═O)NH₂ CH₃ 1 E22 a, b,c, d, e, or f C(═O)NHCH₃ CH₃ 1 E23 a, b, c, d, e, or f CH₂C(═O)NH₂ CH₃ 1E24 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 1 E25 a, b, c, d, e, or fCH₂CH₂C(═O)NH₂ CH₃ 1 E26 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ CH₃ 1 E27c or f H H 2 E28 c or f C(═O)OH H 2 E29 c or f C(═O)OCH₃ H 2 E30 c or fCH₂C(═O)OH H 2 E31 c or f CH₂C(═O)OCH₃ H 2 E32 c or f CH₂CH₂C(═O)OH H 2E33 c or f CH₂CH₂C(═O)OCH₃ H 2 E34 c or f C(═O)NH₂ H 2 E35 c or fC(═O)NHCH₃ H 2 E36 c or f CH₂C(═O)NH₂ H 2 E37 c or f CH₂C(═O)NHCH₃ H 2E38 c or f CH₂CH₂C(═O)NH₂ H 2 E39 c or f CH₂CH₂C(═O)NHCH₃ H 2 E40 a, b,c, d, e, or f H CH₃ 2 E41 a, b, c, d, e, or f C(═O)OH CH₃ 2 E42 a, b, c,d, e, or f C(═O)OCH₃ CH₃ 2 E43 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 2 E44a, b, c, d, e, or f CH₂C(═O)OCH₃ CH₃ 2 E45 a, b, c, d, e, or fCH₂CH₂C(═O)OH CH₃ 2 E46 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 2 E47 a,b, c, d, e, or f C(═O)NH₂ CH₃ 2 E48 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 2E49 a, b, c, d, e, or f CH₂C(═O)NH₂ CH₃ 2 E50 a, b, c, d, e, or fCH₂C(═O)NHCH₃ CH₃ 2 E51 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 2 E52 a,b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ CH₃ 2 E53 c or f H H 3 E54 c or fC(═O)OH H 3 E55 c or f C(═O)OCH₃ H 3 E56 c or f CH₂C(═O)OH H 3 E57 c orf CH₂C(═O)OCH₃ H 3 E58 c or f CH₂CH₂C(═O)OH H 3 E59 c or fCH₂CH₂C(═O)OCH₃ H 3 E60 c or f C(═O)NH₂ H 3 E61 c or f C(═O)NHCH₃ H 3E62 c or f CH₂C(═O)NH₂ H 3 E63 c or f CH₂C(═O)NHCH₃ H 3 E64 c or fCH₂CH₂C(═O)NH₂ H 3 E65 c or f CH₂CH₂C(═O)NHCH₃ H 3 E66 a, b, c, d, e, orf H CH₃ 3 E67 a, b, c, d, e, or f C(═O)OH CH₃ 3 E68 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 3 E69 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 3 E70 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 3 E71 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 3E72 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 3 E73 a, b, c, d, e, or fC(═O)NH₂ CH₃ 3 E74 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 3 E75 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 3 E76 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 3E77 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 3 E78 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atom thatis bonded to the 5-membered, nitrogen-containing ring that is fused tobenzo is in the (R)-conformation, (ii) indicates that Q_(x) ring carbonatom that is bonded to the 5-membered, nitrogen-containing ring that isfused to benzo is in the (S)-conformation.

TABLE 7

(a)

(b)

(c)

(d)

(e)

(f)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) R^(8a) y F F1 c or f H H 1 F2 c or f C(═O)OH H 1 F3 cor f C(═O)OCH₃ H 1 F4 c or f CH₂C(═O)OH H 1 F5 c or f CH₂C(═O)OCH₃ H 1F6 c or f CH₂CH₂C(═O)OH H 1 F7 c or f CH₂CH₂C(═O)OCH₃ H 1 F8 c or fC(═O)NH₂ H 1 F9 c or f C(═O)NHCH₃ H 1 F10 c or f CH₂C(═O)NH₂ H 1 F11 cor f CH₂C(═O)NHCH₃ H 1 F12 c or f CH₂CH₂C(═O)NH₂ H 1 F13 c or fCH₂CH₂C(═O)NHCH₃ H 1 F14 a, b, c, d, e, or f H CH₃ 1 F15 a, b, c, d, e,or f C(═O)OH CH₃ 1 F16 a, b, c, d, e, or f C(═O)OCH₃ CH₃ 1 F17 a, b, c,d, e, or f CH₂C(═O)OH CH₃ 1 F18 a, b, c, d, e, or f CH₂C(═O)OCH₃ CH₃ 1F19 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 1 F20 a, b, c, d, e, or fCH₂CH₂C(═O)OCH₃ CH₃ 1 F21 a, b, c, d, e, or f C(═O)NH₂ CH₃ 1 F22 a, b,c, d, e, or f C(═O)NHCH₃ CH₃ 1 F23 a, b, c, d, e, or f CH₂C(═O)NH₂ CH₃ 1F24 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 1 F25 a, b, c, d, e, or fCH₂CH₂C(═O)NH₂ CH₃ 1 F26 a, b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ CH₃ 1 F27c or f H H 2 F28 c or f C(═O)OH H 2 F29 c or f C(═O)OCH₃ H 2 F30 c or fCH₂C(═O)OH H 2 F31 c or f CH₂C(═O)OCH₃ H 2 F32 c or f CH₂CH₂C(═O)OH H 2F33 c or f CH₂CH₂C(═O)OCH₃ H 2 F34 c or f C(═O)NH₂ H 2 F35 c or fC(═O)NHCH₃ H 2 F36 c or f CH₂C(═O)NH₂ H 2 F37 c or f CH₂C(═O)NHCH₃ H 2F38 c or f CH₂CH₂C(═O)NH₂ H 2 F39 c or f CH₂CH₂C(═O)NHCH₃ H 2 F40 a, b,c, d, e, or f H CH₃ 2 F41 a, b, c, d, e, or f C(═O)OH CH₃ 2 F42 a, b, c,d, e, or f C(═O)OCH₃ CH₃ 2 F43 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 2 F44a, b, c, d, e, or f CH₂C(═O)OCH₃ CH₃ 2 F45 a, b, c, d, e, or fCH₂CH₂C(═O)OH CH₃ 2 F46 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 2 F47 a,b, c, d, e, or f C(═O)NH₂ CH₃ 2 F48 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 2F49 a, b, c, d, e, or f CH₂C(═O)NH₂ CH₃ 2 F50 a, b, c, d, e, or fCH₂C(═O)NHCH₃ CH₃ 2 F51 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 2 F52 a,b, c, d, e, or f CH₂CH₂C(═O)NHCH₃ CH₃ 2 F53 c or f H H 3 F54 c or fC(═O)OH H 3 F55 c or f C(═O)OCH₃ H 3 F56 c or f CH₂C(═O)OH H 3 F57 c orf CH₂C(═O)OCH₃ H 3 F58 c or f CH₂CH₂C(═O)OH H 3 F59 c or fCH₂CH₂C(═O)OCH₃ H 3 F60 c or f C(═O)NH₂ H 3 F61 c or f C(═O)NHCH₃ H 3F62 c or f CH₂C(═O)NH₂ H 3 F63 c or f CH₂C(═O)NHCH₃ H 3 F64 c or fCH₂CH₂C(═O)NH₂ H 3 F65 c or f CH₂CH₂C(═O)NHCH₃ H 3 F66 a, b, c, d, e, orf H CH₃ 3 F67 a, b, c, d, e, or f C(═O)OH CH₃ 3 F68 a, b, c, d, e, or fC(═O)OCH₃ CH₃ 3 F69 a, b, c, d, e, or f CH₂C(═O)OH CH₃ 3 F70 a, b, c, d,e, or f CH₂C(═O)OCH₃ CH₃ 3 F71 a, b, c, d, e, or f CH₂CH₂C(═O)OH CH₃ 3F72 a, b, c, d, e, or f CH₂CH₂C(═O)OCH₃ CH₃ 3 F73 a, b, c, d, e, or fC(═O)NH₂ CH₃ 3 F74 a, b, c, d, e, or f C(═O)NHCH₃ CH₃ 3 F75 a, b, c, d,e, or f CH₂C(═O)NH₂ CH₃ 3 F76 a, b, c, d, e, or f CH₂C(═O)NHCH₃ CH₃ 3F77 a, b, c, d, e, or f CH₂CH₂C(═O)NH₂ CH₃ 3 F78 a, b, c, d, e, or fCH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atom thatis bonded to the 5-membered, nitrogen-containing ring that is fused tobenzo is in the (R)-conformation, (ii) indicates that Q_(x) ring carbonatom that is bonded to the 5-membered, nitrogen-containing ring that isfused to benzo is in the (S)-conformation.

TABLE 8

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) R^(8a) y G G1 a, b, c, or d H H 1 G2 a, b, c, or dC(═O)OH H 1 G3 a, b, c, or d C(═O)OCH₃ H 1 G4 a, b, c, or d CH₂C(═O)OH H1 G5 a, b, c, or d CH₂C(═O)OCH₃ H 1 G6 a, b, c, or d CH₂CH₂C(═O)OH H 1G7 a, b, c, or d CH₂CH₂C(═O)OCH₃ H 1 G8 a, b, c, or d C(═O)NH₂ H 1 G9 a,b, c, or d C(═O)NHCH₃ H 1 G10 a, b, c, or d CH₂C(═O)NH₂ H 1 G11 a, b, c,or d CH₂C(═O)NHCH₃ H 1 G12 a, b, c, or d CH₂CH₂C(═O)NH₂ H 1 G13 a, b, c,or d CH₂CH₂C(═O)NHCH₃ H 1 G14 a, b, c, or d H CH₃ 1 G15 a, b, c, or dC(═O)OH CH₃ 1 G16 a, b, c, or d C(═O)OCH₃ CH₃ 1 G17 a, b, c, or dCH₂C(═O)OH CH₃ 1 G18 a, b, c, or d CH₂C(═O)OCH₃ CH₃ 1 G19 a, b, c, or dCH₂CH₂C(═O)OH CH₃ 1 G20 a, b, c, or d CH₂CH₂C(═O)OCH₃ CH₃ 1 G21 a, b, c,or d C(═O)NH₂ CH₃ 1 G22 a, b, c, or d C(═O)NHCH₃ CH₃ 1 G23 a, b, c, or dCH₂C(═O)NH₂ CH₃ 1 G24 a, b, c, or d CH₂C(═O)NHCH₃ CH₃ 1 G25 a, b, c, ord CH₂CH₂C(═O)NH₂ CH₃ 1 G26 a, b, c, or d CH₂CH₂C(═O)NHCH₃ CH₃ 1 G27 a,b, c, or d H H 2 G28 a, b, c, or d C(═O)OH H 2 G29 a, b, c, or dC(═O)OCH₃ H 2 G30 a, b, c, or d CH₂C(═O)OH H 2 G31 a, b, c, or dCH₂C(═O)OCH₃ H 2 G32 a, b, c, or d CH₂CH₂C(═O)OH H 2 G33 a, b, c, or dCH₂CH₂C(═O)OCH₃ H 2 G34 a, b, c, or d C(═O)NH₂ H 2 G35 a, b, c, or dC(═O)NHCH₃ H 2 G36 a, b, c, or d CH₂C(═O)NH₂ H 2 G37 a, b, c, or dCH₂C(═O)NHCH₃ H 2 G38 a, b, c, or d CH₂CH₂C(═O)NH₂ H 2 G39 a, b, c, or dCH₂CH₂C(═O)NHCH₃ H 2 G40 a, b, c, or d H CH₃ 2 G41 a, b, c, or d C(═O)OHCH₃ 2 G42 a, b, c, or d C(═O)OCH₃ CH₃ 2 G43 a, b, c, or d CH₂C(═O)OH CH₃2 G44 a, b, c, or d CH₂C(═O)OCH₃ CH₃ 2 G45 a, b, c, or d CH₂CH₂C(═O)OHCH₃ 2 G46 a, b, c, or d CH₂CH₂C(═O)OCH₃ CH₃ 2 G47 a, b, c, or d C(═O)NH₂CH₃ 2 G48 a, b, c, or d C(═O)NHCH₃ CH₃ 2 G49 a, b, c, or d CH₂C(═O)NH₂CH₃ 2 G50 a, b, c, or d CH₂C(═O)NHCH₃ CH₃ 2 G51 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₃ 2 G52 a, b, c, or d CH₂CH₂C(═O)NHCH₃ CH₃ 2 G53 a, b,c, or d H H 3 G54 a, b, c, or d C(═O)OH H 3 G55 a, b, c, or d C(═O)OCH₃H 3 G56 a, b, c, or d CH₂C(═O)OH H 3 G57 a, b, c, or d CH₂C(═O)OCH₃ H 3G58 a, b, c, or d CH₂CH₂C(═O)OH H 3 G59 a, b, c, or d CH₂CH₂C(═O)OCH₃ H3 G60 a, b, c, or d C(═O)NH₂ H 3 G61 a, b, c, or d C(═O)NHCH₃ H 3 G62 a,b, c, or d CH₂C(═O)NH₂ H 3 G63 a, b, c, or d CH₂C(═O)NHCH₃ H 3 G64 a, b,c, or d CH₂CH₂C(═O)NH₂ H 3 G65 a, b, c, or d CH₂CH₂C(═O)NHCH₃ H 3 G66 a,b, c, or d H CH₃ 3 G67 a, b, c, or d C(═O)OH CH₃ 3 G68 a, b, c, or dC(═O)OCH₃ CH₃ 3 G69 a, b, c, or d CH₂C(═O)OH CH₃ 3 G70 a, b, c, or dCH₂C(═O)OCH₃ CH₃ 3 G71 a, b, c, or d CH₂CH₂C(═O)OH CH₃ 3 G72 a, b, c, ord CH₂CH₂C(═O)OCH₃ CH₃ 3 G73 a, b, c, or d C(═O)NH₂ CH₃ 3 G74 a, b, c, ord C(═O)NHCH₃ CH₃ 3 G75 a, b, c, or d CH₂C(═O)NH₂ CH₃ 3 G76 a, b, c, or dCH₂C(═O)NHCH₃ CH₃ 3 G77 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₃ 3 G78 a, b, c,or d CH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atomthat is bonded to the 5-membered, nitrogen-containing ring that is fusedto benzo is in the (R)-conformation, (ii) indicates that Q_(x) ringcarbon atom that is bonded to the 5-membered, nitrogen-containing ringthat is fused to benzo is in the (S)-conformation.

TABLE 9

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) R^(8a) y H H1 a, b, c, or d H H 1 H2 a, b, c, or dC(═O)OH H 1 H3 a, b, c, or d C(═O)OCH₃ H 1 H4 a, b, c, or d CH₂C(═O)OH H1 H5 a, b, c, or d CH₂C(═O)OCH₃ H 1 H6 a, b, c, or d CH₂CH₂C(═O)OH H 1H7 a, b, c, or d CH₂CH₂C(═O)OCH₃ H 1 H8 a, b, c, or d C(═O)NH₂ H 1 H9 a,b, c, or d C(═O)NHCH₃ H 1 H10 a, b, c, or d CH₂C(═O)NH₂ H 1 H11 a, b, c,or d CH₂C(═O)NHCH₃ H 1 H12 a, b, c, or d CH₂CH₂C(═O)NH₂ H 1 H13 a, b, c,or d CH₂CH₂C(═O)NHCH₃ H 1 H14 a, b, c, or d H CH₃ 1 H15 a, b, c, or dC(═O)OH CH₃ 1 H16 a, b, c, or d C(═O)OCH₃ CH₃ 1 H17 a, b, c, or dCH₂C(═O)OH CH₃ 1 H18 a, b, c, or d CH₂C(═O)OCH₃ CH₃ 1 H19 a, b, c, or dCH₂CH₂C(═O)OH CH₃ 1 H20 a, b, c, or d CH₂CH₂C(═O)OCH₃ CH₃ 1 H21 a, b, c,or d C(═O)NH₂ CH₃ 1 H22 a, b, c, or d C(═O)NHCH₃ CH₃ 1 H23 a, b, c, or dCH₂C(═O)NH₂ CH₃ 1 H24 a, b, c, or d CH₂C(═O)NHCH₃ CH₃ 1 H25 a, b, c, ord CH₂CH₂C(═O)NH₂ CH₃ 1 H26 a, b, c, or d CH₂CH₂C(═O)NHCH₃ CH₃ 1 H27 a,b, c, or d H H 2 H28 a, b, c, or d C(═O)OH H 2 H29 a, b, c, or dC(═O)OCH₃ H 2 H30 a, b, c, or d CH₂C(═O)OH H 2 H31 a, b, c, or dCH₂C(═O)OCH₃ H 2 H32 a, b, c, or d CH₂CH₂C(═O)OH H 2 H33 a, b, c, or dCH₂CH₂C(═O)OCH₃ H 2 H34 a, b, c, or d C(═O)NH₂ H 2 H35 a, b, c, or dC(═O)NHCH₃ H 2 H36 a, b, c, or d CH₂C(═O)NH₂ H 2 H37 a, b, c, or dCH₂C(═O)NHCH₃ H 2 H38 a, b, c, or d CH₂CH₂C(═O)NH₂ H 2 H39 a, b, c, or dCH₂CH₂C(═O)NHCH₃ H 2 H40 a, b, c, or d H CH₃ 2 H41 a, b, c, or d C(═O)OHCH₃ 2 H42 a, b, c, or d C(═O)OCH₃ CH₃ 2 H43 a, b, c, or d CH₂C(═O)OH CH₃2 H44 a, b, c, or d CH₂C(═O)OCH₃ CH₃ 2 H45 a, b, c, or d CH₂CH₂C(═O)OHCH₃ 2 H46 a, b, c, or d CH₂CH₂C(═O)OCH₃ CH₃ 2 H47 a, b, c, or d C(═O)NH₂CH₃ 2 H48 a, b, c, or d C(═O)NHCH₃ CH₃ 2 H49 a, b, c, or d CH₂C(═O)NH₂CH₃ 2 H50 a, b, c, or d CH₂C(═O)NHCH₃ CH₃ 2 H51 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₃ 2 H52 a, b, c, or d CH₂CH₂C(═O)NHCH₃ CH₃ 2 H53 a, b,c, or d H H 3 H54 a, b, c, or d C(═O)OH H 3 H55 a, b, c, or d C(═O)OCH₃H 3 H56 a, b, c, or d CH₂C(═O)OH H 3 H57 a, b, c, or d CH₂C(═O)OCH₃ H 3H58 a, b, c, or d CH₂CH₂C(═O)OH H 3 H59 a, b, c, or d CH₂CH₂C(═O)OCH₃ H3 H60 a, b, c, or d C(═O)NH₂ H 3 H61 a, b, c, or d C(═O)NHCH₃ H 3 H62 a,b, c, or d CH₂C(═O)NH₂ H 3 H63 a, b, c, or d CH₂C(═O)NHCH₃ H 3 H64 a, b,c, or d CH₂CH₂C(═O)NH₂ H 3 H65 a, b, c, or d CH₂CH₂C(═O)NHCH₃ H 3 H66 a,b, c, or d H CH₃ 3 H67 a, b, c, or d C(═O)OH CH₃ 3 H68 a, b, c, or dC(═O)OCH₃ CH₃ 3 H69 a, b, c, or d CH₂C(═O)OH CH₃ 3 H70 a, b, c, or dCH₂C(═O)OCH₃ CH₃ 3 H71 a, b, c, or d CH₂CH₂C(═O)OH CH₃ 3 H72 a, b, c, ord CH₂CH₂C(═O)OCH₃ CH₃ 3 H73 a, b, c, or d C(═O)NH₂ CH₃ 3 H74 a, b, c, ord C(═O)NHCH₃ CH₃ 3 H75 a, b, c, or d CH₂C(═O)NH₂ CH₃ 3 H76 a, b, c, or dCH₂C(═O)NHCH₃ CH₃ 3 H77 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₃ 3 H78 a, b, c,or d CH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atomthat is bonded to the 5-membered, nitrogen-containing ring that is fusedto benzo is in the (R)-conformation, (ii) indicates that Q_(x) ringcarbon atom that is bonded to the 5-membered, nitrogen-containing ringthat is fused to benzo is in the (S)-conformation.

TABLE 10

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound* R^(4a) R^(8a) y J J1 a, b, c, or d H H 1 J2 a, b, c, or dC(═O)OH H 1 J3 a, b, c, or d C(═O)OCH₃ H 1 J4 a, b, c, or d CH₂C(═O)OH H1 J5 a, b, c, or d CH₂C(═O)OCH₃ H 1 J6 a, b, c, or d CH₂CH₂C(═O)OH H 1J7 a, b, c, or d CH₂CH₂C(═O)OCH₃ H 1 J8 a, b, c, or d C(═O)NH₂ H 1 J9 a,b, c, or d C(═O)NHCH₃ H 1 J10 a, b, c, or d CH₂C(═O)NH₂ H 1 J11 a, b, c,or d CH₂C(═O)NHCH₃ H 1 J12 a, b, c, or d CH₂CH₂C(═O)NH₂ H 1 J13 a, b, c,or d CH₂CH₂C(═O)NHCH₃ H 1 J14 a, b, c, or d H CH₃ 1 J15 a, b, c, or dC(═O)OH CH₃ 1 J16 a, b, c, or d C(═O)OCH₃ CH₃ 1 J17 a, b, c, or dCH₂C(═O)OH CH₃ 1 J18 a, b, c, or d CH₂C(═O)OCH₃ CH₃ 1 J19 a, b, c, or dCH₂CH₂C(═O)OH CH₃ 1 J20 a, b, c, or d CH₂CH₂C(═O)OCH₃ CH₃ 1 J21 a, b, c,or d C(═O)NH₂ CH₃ 1 J22 a, b, c, or d C(═O)NHCH₃ CH₃ 1 J23 a, b, c, or dCH₂C(═O)NH₂ CH₃ 1 J24 a, b, c, or d CH₂C(═O)NHCH₃ CH₃ 1 J25 a, b, c, ord CH₂CH₂C(═O)NH₂ CH₃ 1 J26 a, b, c, or d CH₂CH₂C(═O)NHCH₃ CH₃ 1 J27 a,b, c, or d H H 2 J28 a, b, c, or d C(═O)OH H 2 J29 a, b, c, or dC(═O)OCH₃ H 2 J30 a, b, c, or d CH₂C(═O)OH H 2 J31 a, b, c, or dCH₂C(═O)OCH₃ H 2 J32 a, b, c, or d CH₂CH₂C(═O)OH H 2 J33 a, b, c, or dCH₂CH₂C(═O)OCH₃ H 2 J34 a, b, c, or d C(═O)NH₂ H 2 J35 a, b, c, or dC(═O)NHCH₃ H 2 J36 a, b, c, or d CH₂C(═O)NH₂ H 2 J37 a, b, c, or dCH₂C(═O)NHCH₃ H 2 J38 a, b, c, or d CH₂CH₂C(═O)NH₂ H 2 J39 a, b, c, or dCH₂CH₂C(═O)NHCH₃ H 2 J40 a, b, c, or d H CH₃ 2 J41 a, b, c, or d C(═O)OHCH₃ 2 J42 a, b, c, or d C(═O)OCH₃ CH₃ 2 J43 a, b, c, or d CH₂C(═O)OH CH₃2 J44 a, b, c, or d CH₂C(═O)OCH₃ CH₃ 2 J45 a, b, c, or d CH₂CH₂C(═O)OHCH₃ 2 J46 a, b, c, or d CH₂CH₂C(═O)OCH₃ CH₃ 2 J47 a, b, c, or d C(═O)NH₂CH₃ 2 J48 a, b, c, or d C(═O)NHCH₃ CH₃ 2 J49 a, b, c, or d CH₂C(═O)NH₂CH₃ 2 J50 a, b, c, or d CH₂C(═O)NHCH₃ CH₃ 2 J51 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₃ 2 J52 a, b, c, or d CH₂CH₂C(═O)NHCH₃ CH₃ 2 J53 a, b,c, or d H H 3 J54 a, b, c, or d C(═O)OH H 3 J55 a, b, c, or d C(═O)OCH₃H 3 J56 a, b, c, or d CH₂C(═O)OH H 3 J57 a, b, c, or d CH₂C(═O)OCH₃ H 3J58 a, b, c, or d CH₂CH₂C(═O)OH H 3 J59 a, b, c, or d CH₂CH₂C(═O)OCH₃ H3 J60 a, b, c, or d C(═O)NH₂ H 3 J61 a, b, c, or d C(═O)NHCH₃ H 3 J62 a,b, c, or d CH₂C(═O)NH₂ H 3 J63 a, b, c, or d CH₂C(═O)NHCH₃ H 3 J64 a, b,c, or d CH₂CH₂C(═O)NH₂ H 3 J65 a, b, c, or d CH₂CH₂C(═O)NHCH₃ H 3 J66 a,b, c, or d H CH₃ 3 J67 a, b, c, or d C(═O)OH CH₃ 3 J68 a, b, c, or dC(═O)OCH₃ CH₃ 3 J69 a, b, c, or d CH₂C(═O)OH CH₃ 3 J70 a, b, c, or dCH₂C(═O)OCH₃ CH₃ 3 J71 a, b, c, or d CH₂CH₂C(═O)OH CH₃ 3 J72 a, b, c, ord CH₂CH₂C(═O)OCH₃ CH₃ 3 J73 a, b, c, or d C(═O)NH₂ CH₃ 3 J74 a, b, c, ord C(═O)NHCH₃ CH₃ 3 J75 a, b, c, or d CH₂C(═O)NH₂ CH₃ 3 J76 a, b, c, or dCH₂C(═O)NHCH₃ CH₃ 3 J77 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₃ 3 J78 a, b, c,or d CH₂CH₂C(═O)NHCH₃ CH₃ 3 *(i) Indicates that Q_(x) ring carbon atomthat is bonded to the 5-membered, nitrogen-containing ring that is fusedto benzo is in the (R)-conformation, (ii) indicates that Q_(x) ringcarbon atom that is bonded to the 5-membered, nitrogen-containing ringthat is fused to benzo is in the (S)-conformation.

TABLE 11

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound R^(4a) R^(3a) R^(8a) y K K1 a, b, c, or d H H H 1 K2 a, b, c,or d CH₂C(═O)OH H H 1 K3 a, b, c, or d CH₂C(═O)OCH₃ H H 1 K4 a, b, c, ord CH₂CH₂C(═O)OH H H 1 K5 a, b, c, or d CH₂CH₂C(═O)OCH₃ H H 1 K6 a, b, c,or d CH₂C(═O)NH₂ H H 1 K7 a, b, c, or d CH₂CH₂C(═O)NH₂ H H 1 K8 a, b, c,or d H CH₂C(═O)OH H 1 K9 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH H 1 K10 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H 1 K11 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH H 1 K12 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 1 K13 a, b,c, or d H CH₂C(═O)NH₂ H 1 K14 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 1K15 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 1 K16 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 1 K17 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 1 K18 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 K19 a, b,c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 K20 a, b, c, or d H H CH₃ 1 K21a, b, c, or d CH₂C(═O)OH H CH₃ 1 K22 a, b, c, or d CH₂C(═O)OCH₃ H CH₃ 1K23 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 1 K24 a, b, c, or dCH₂CH₂C(═O)OCH₃ H CH₃ 1 K25 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 1 K26 a, b,c, or d CH₂CH₂C(═O)NH₂ H CH₃ 1 K27 a, b, c, or d H CH₂C(═O)OH CH₃ 1 K28a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 K29 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 K30 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 1 K31 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 1 K32 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 1 K33 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 K34a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 1 K35 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 K36 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 1 K37 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 K38 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 K39 a, b, c, or d H H H 2K40 a, b, c, or d CH₂C(═O)OH H H 2 K41 a, b, c, or d CH₂C(═O)OCH₃ H H 2K42 a, b, c, or d CH₂CH₂C(═O)OH H H 2 K43 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 2 K44 a, b, c, or d CH₂C(═O)NH₂ H H 2 K45 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 2 K46 a, b, c, or d H CH₂C(═O)OH H 2 K47 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 2 K48 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H2 K49 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 2 K50 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 2 K51 a, b, c, or d H CH₂C(═O)NH₂ H 2 K52 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 2 K53 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 2 K54 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 2 K55 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 2 K56 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 2 K57 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 2 K58 a,b, c, or d H H CH₃ 2 K59 a, b, c, or d CH₂C(═O)OH H CH₃ 2 K60 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 2 K61 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 2 K62 a,b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 2 K63 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 2K64 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 2 K65 a, b, c, or d H CH₂C(═O)OHCH₃ 2 K66 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 K67 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 K68 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 2 K69 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 2 K70 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 2 K71 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 K72a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 2 K73 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 K74 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 2 K75 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 K76 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 K77 a, b, c, or d H H H 3K78 a, b, c, or d CH₂C(═O)OH H H 3 K79 a, b, c, or d CH₂C(═O)OCH₃ H H 3K80 a, b, c, or d CH₂CH₂C(═O)OH H H 3 K81 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 3 K82 a, b, c, or d CH₂C(═O)NH₂ H H 3 K83 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 3 K84 a, b, c, or d H CH₂C(═O)OH H 3 K85 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 3 K86 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H3 K87 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 3 K88 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 3 K89 a, b, c, or d H CH₂C(═O)NH₂ H 3 K90 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 3 K91 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 3 K92 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 3 K93 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 3 K94 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 3 K95 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 3 K96 a,b, c, or d H H CH₃ 3 K97 a, b, c, or d CH₂C(═O)OH H CH₃ 3 K98 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 3 K99 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 3 K100a, b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 3 K101 a, b, c, or d CH₂C(═O)NH₂ HCH₃ 3 K102 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 3 K103 a, b, c, or d HCH₂C(═O)OH CH₃ 3 K104 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 K105 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 K106 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH CH₃ 3 K107 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 3 K108a, b, c, or d H CH₂C(═O)NH₂ CH₃ 3 K109 a, b, c, or d CH₂C(═O)OHCH₂C(═O)NH₂ CH₃ 3 K110 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 K111a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 3 K112 a, b, c, or dCH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 K113 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ CH₃ 3 K114 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 3

TABLE 12

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound R^(4a) R^(3a) R^(8a) y L L1 a, b, c, or d H H H 1 L2 a, b, c,or d CH₂C(═O)OH H H 1 L3 a, b, c, or d CH₂C(═O)OCH₃ H H 1 L4 a, b, c, ord CH₂CH₂C(═O)OH H H 1 L5 a, b, c, or d CH₂CH₂C(═O)OCH₃ H H 1 L6 a, b, c,or d CH₂C(═O)NH₂ H H 1 L7 a, b, c, or d CH₂CH₂C(═O)NH₂ H H 1 L8 a, b, c,or d H CH₂C(═O)OH H 1 L9 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH H 1 L10 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H 1 L11 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH H 1 L12 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 1 L13 a, b,c, or d H CH₂C(═O)NH₂ H 1 L14 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 1L15 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 1 L16 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 1 L17 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 1 L18 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 L19 a, b,c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 L20 a, b, c, or d H H CH₃ 1 L21a, b, c, or d CH₂C(═O)OH H CH₃ 1 L22 a, b, c, or d CH₂C(═O)OCH₃ H CH₃ 1L23 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 1 L24 a, b, c, or dCH₂CH₂C(═O)OCH₃ H CH₃ 1 L25 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 1 L26 a, b,c, or d CH₂CH₂C(═O)NH₂ H CH₃ 1 L27 a, b, c, or d H CH₂C(═O)OH CH₃ 1 L28a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 L29 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 L30 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 1 L31 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 1 L32 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 1 L33 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 L34a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 1 L35 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 L36 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 1 L37 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 L38 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 L39 a, b, c, or d H H H 2L40 a, b, c, or d CH₂C(═O)OH H H 2 L41 a, b, c, or d CH₂C(═O)OCH₃ H H 2L42 a, b, c, or d CH₂CH₂C(═O)OH H H 2 L43 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 2 L44 a, b, c, or d CH₂C(═O)NH₂ H H 2 L45 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 2 L46 a, b, c, or d H CH₂C(═O)OH H 2 L47 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 2 L48 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H2 L49 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 2 L50 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 2 L51 a, b, c, or d H CH₂C(═O)NH₂ H 2 L52 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 2 L53 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 2 L54 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 2 L55 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 2 L56 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 2 L57 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 2 L58 a,b, c, or d H H CH₃ 2 L59 a, b, c, or d CH₂C(═O)OH H CH₃ 2 L60 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 2 L61 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 2 L62 a,b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 2 L63 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 2L64 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 2 L65 a, b, c, or d H CH₂C(═O)OHCH₃ 2 L66 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 L67 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 L68 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 2 L69 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 2 L70 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 2 L71 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 L72a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 2 L73 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 L74 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 2 L75 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 L76 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 L77 a, b, c, or d H H H 3L78 a, b, c, or d CH₂C(═O)OH H H 3 L79 a, b, c, or d CH₂C(═O)OCH₃ H H 3L80 a, b, c, or d CH₂CH₂C(═O)OH H H 3 L81 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 3 L82 a, b, c, or d CH₂C(═O)NH₂ H H 3 L83 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 3 L84 a, b, c, or d H CH₂C(═O)OH H 3 L85 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 3 L86 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H3 L87 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 3 L88 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 3 L89 a, b, c, or d H CH₂C(═O)NH₂ H 3 L90 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 3 L91 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 3 L92 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 3 L93 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 3 L94 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 3 L95 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 3 L96 a,b, c, or d H H CH₃ 3 L97 a, b, c, or d CH₂C(═O)OH H CH₃ 3 L98 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 3 L99 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 3 L100a, b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 3 L101 a, b, c, or d CH₂C(═O)NH₂ HCH₃ 3 L102 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 3 L103 a, b, c, or d HCH₂C(═O)OH CH₃ 3 L104 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 L105 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 L106 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH CH₃ 3 L107 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 3 L108a, b, c, or d H CH₂C(═O)NH₂ CH₃ 3 L109 a, b, c, or d CH₂C(═O)OHCH₂C(═O)NH₂ CH₃ 3 L110 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 L111a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 3 L112 a, b, c, or dCH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 L113 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ CH₃ 3 L114 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 3

TABLE 13

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound R^(4a) R^(3a) R^(8a) y M M1 a, b, c, or d H H H 1 M2 a, b, c,or d CH₂C(═O)OH H H 1 M3 a, b, c, or d CH₂C(═O)OCH₃ H H 1 M4 a, b, c, ord CH₂CH₂C(═O)OH H H 1 M5 a, b, c, or d CH₂CH₂C(═O)OCH₃ H H 1 M6 a, b, c,or d CH₂C(═O)NH₂ H H 1 M7 a, b, c, or d CH₂CH₂C(═O)NH₂ H H 1 M8 a, b, c,or d H CH₂C(═O)OH H 1 M9 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH H 1 M10 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H 1 M11 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH H 1 M12 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 1 M13 a, b,c, or d H CH₂C(═O)NH₂ H 1 M14 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 1M15 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 1 M16 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 1 M17 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 1 M18 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 M19 a, b,c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 M20 a, b, c, or d H H CH₃ 1 M21a, b, c, or d CH₂C(═O)OH H CH₃ 1 M22 a, b, c, or d CH₂C(═O)OCH₃ H CH₃ 1M23 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 1 M24 a, b, c, or dCH₂CH₂C(═O)OCH₃ H CH₃ 1 M25 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 1 M26 a, b,c, or d CH₂CH₂C(═O)NH₂ H CH₃ 1 M27 a, b, c, or d H CH₂C(═O)OH CH₃ 1 M28a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 M29 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 M30 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 1 M31 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 1 M32 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 1 M33 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 M34a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 1 M35 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 M36 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 1 M37 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 M38 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 M39 a, b, c, or d H H H 2M40 a, b, c, or d CH₂C(═O)OH H H 2 M41 a, b, c, or d CH₂C(═O)OCH₃ H H 2M42 a, b, c, or d CH₂CH₂C(═O)OH H H 2 M43 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 2 M44 a, b, c, or d CH₂C(═O)NH₂ H H 2 M45 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 2 M46 a, b, c, or d H CH₂C(═O)OH H 2 M47 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 2 M48 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H2 M49 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 2 M50 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 2 M51 a, b, c, or d H CH₂C(═O)NH₂ H 2 M52 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 2 M53 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 2 M54 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 2 M55 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 2 M56 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 2 M57 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 2 M58 a,b, c, or d H H CH₃ 2 M59 a, b, c, or d CH₂C(═O)OH H CH₃ 2 M60 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 2 M61 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 2 M62 a,b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 2 M63 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 2M64 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 2 M65 a, b, c, or d H CH₂C(═O)OHCH₃ 2 M66 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 M67 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 M68 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 2 M69 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 2 M70 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 2 M71 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 M72a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 2 M73 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 M74 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 2 M75 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 M76 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 M77 a, b, c, or d H H H 3M78 a, b, c, or d CH₂C(═O)OH H H 3 M79 a, b, c, or d CH₂C(═O)OCH₃ H H 3M80 a, b, c, or d CH₂CH₂C(═O)OH H H 3 M81 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 3 M82 a, b, c, or d CH₂C(═O)NH₂ H H 3 M83 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 3 M84 a, b, c, or d H CH₂C(═O)OH H 3 M85 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 3 M86 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H3 M87 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 3 M88 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 3 M89 a, b, c, or d H CH₂C(═O)NH₂ H 3 M90 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 3 M91 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 3 M92 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 3 M93 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 3 M94 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 3 M95 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 3 M96 a,b, c, or d H H CH₃ 3 M97 a, b, c, or d CH₂C(═O)OH H CH₃ 3 M98 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 3 M99 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 3 M100a, b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 3 M101 a, b, c, or d CH₂C(═O)NH₂ HCH₃ 3 M102 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 3 M103 a, b, c, or d HCH₂C(═O)OH CH₃ 3 M104 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 M105 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 M106 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH CH₃ 3 M107 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 3 M108a, b, c, or d H CH₂C(═O)NH₂ CH₃ 3 M109 a, b, c, or d CH₂C(═O)OHCH₂C(═O)NH₂ CH₃ 3 M110 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 M111a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 3 M112 a, b, c, or dCH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 M113 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ CH₃ 3 M114 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 3

TABLE 14

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound R^(4a) R^(3a) R^(8a) y N N1 a, b, c, or d H H H 1 N2 a, b, c,or d CH₂C(═O)OH H H 1 N3 a, b, c, or d CH₂C(═O)OCH₃ H H 1 N4 a, b, c, ord CH₂CH₂C(═O)OH H H 1 N5 a, b, c, or d CH₂CH₂C(═O)OCH₃ H H 1 N6 a, b, c,or d CH₂C(═O)NH₂ H H 1 N7 a, b, c, or d CH₂CH₂C(═O)NH₂ H H 1 N8 a, b, c,or d H CH₂C(═O)OH H 1 N9 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH H 1 N10 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H 1 N11 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH H 1 N12 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 1 N13 a, b,c, or d H CH₂C(═O)NH₂ H 1 N14 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 1N15 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 1 N16 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 1 N17 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 1 N18 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 N19 a, b,c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 N20 a, b, c, or d H H CH₃ 1 N21a, b, c, or d CH₂C(═O)OH H CH₃ 1 N22 a, b, c, or d CH₂C(═O)OCH₃ H CH₃ 1N23 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 1 N24 a, b, c, or dCH₂CH₂C(═O)OCH₃ H CH₃ 1 N25 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 1 N26 a, b,c, or d CH₂CH₂C(═O)NH₂ H CH₃ 1 N27 a, b, c, or d H CH₂C(═O)OH CH₃ 1 N28a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 N29 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 N30 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 1 N31 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 1 N32 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 1 N33 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 N34a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 1 N35 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 N36 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 1 N37 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 N38 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 N39 a, b, c, or d H H H 2N40 a, b, c, or d CH₂C(═O)OH H H 2 N41 a, b, c, or d CH₂C(═O)OCH₃ H H 2N42 a, b, c, or d CH₂CH₂C(═O)OH H H 2 N43 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 2 N44 a, b, c, or d CH₂C(═O)NH₂ H H 2 N45 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 2 N46 a, b, c, or d H CH₂C(═O)OH H 2 N47 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 2 N48 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H2 N49 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 2 N50 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 2 N51 a, b, c, or d H CH₂C(═O)NH₂ H 2 N52 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 2 N53 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 2 N54 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 2 N55 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 2 N56 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 2 N57 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 2 N58 a,b, c, or d H H CH₃ 2 N59 a, b, c, or d CH₂C(═O)OH H CH₃ 2 N60 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 2 N61 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 2 N62 a,b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 2 N63 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 2N64 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 2 N65 a, b, c, or d H CH₂C(═O)OHCH₃ 2 N66 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 N67 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 N68 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 2 N69 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 2 N70 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 2 N71 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 N72a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 2 N73 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 N74 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 2 N75 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 N76 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 N77 a, b, c, or d H H H 3N78 a, b, c, or d CH₂C(═O)OH H H 3 N79 a, b, c, or d CH₂C(═O)OCH₃ H H 3N80 a, b, c, or d CH₂CH₂C(═O)OH H H 3 N81 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 3 N82 a, b, c, or d CH₂C(═O)NH₂ H H 3 N83 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 3 N84 a, b, c, or d H CH₂C(═O)OH H 3 N85 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 3 N86 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H3 N87 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 3 N88 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 3 N89 a, b, c, or d H CH₂C(═O)NH₂ H 3 N90 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 3 N91 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 3 N92 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 3 N93 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 3 N94 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 3 N95 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 3 N96 a,b, c, or d H H CH₃ 3 N97 a, b, c, or d CH₂C(═O)OH H CH₃ 3 N98 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 3 N99 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 3 N100a, b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 3 N101 a, b, c, or d CH₂C(═O)NH₂ HCH₃ 3 N102 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 3 N103 a, b, c, or d HCH₂C(═O)OH CH₃ 3 N104 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 N105 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 N106 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH CH₃ 3 N107 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 3 N108a, b, c, or d H CH₂C(═O)NH₂ CH₃ 3 N109 a, b, c, or d CH₂C(═O)OHCH₂C(═O)NH₂ CH₃ 3 N110 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 N111a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 3 N112 a, b, c, or dCH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 N113 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ CH₃ 3 N114 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 3

TABLE 15

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound R^(4a) R^(3a) R^(8a) y O O1 a, b, c, or d H H H 1 O2 a, b, c,or d CH₂C(═O)OH H H 1 O3 a, b, c, or d CH₂C(═O)OCH₃ H H 1 O4 a, b, c, ord CH₂CH₂C(═O)OH H H 1 O5 a, b, c, or d CH₂CH₂C(═O)OCH₃ H H 1 O6 a, b, c,or d CH₂C(═O)NH₂ H H 1 O7 a, b, c, or d CH₂CH₂C(═O)NH₂ H H 1 O8 a, b, c,or d H CH₂C(═O)OH H 1 O9 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH H 1 O10 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H 1 O11 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH H 1 O12 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 1 O13 a, b,c, or d H CH₂C(═O)NH₂ H 1 O14 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 1O15 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 1 O16 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 1 O17 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 1 O18 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 O19 a, b,c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 O20 a, b, c, or d H H CH₃ 1 O21a, b, c, or d CH₂C(═O)OH H CH₃ 1 O22 a, b, c, or d CH₂C(═O)OCH₃ H CH₃ 1O23 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 1 O24 a, b, c, or dCH₂CH₂C(═O)OCH₃ H CH₃ 1 O25 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 1 O26 a, b,c, or d CH₂CH₂C(═O)NH₂ H CH₃ 1 O27 a, b, c, or d H CH₂C(═O)OH CH₃ 1 O28a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 O29 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 O30 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 1 O31 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 1 O32 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 1 O33 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 O34a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 1 O35 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 O36 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 1 O37 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 O38 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 O39 a, b, c, or d H H H 2O40 a, b, c, or d CH₂C(═O)OH H H 2 O41 a, b, c, or d CH₂C(═O)OCH₃ H H 2O42 a, b, c, or d CH₂CH₂C(═O)OH H H 2 O43 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 2 O44 a, b, c, or d CH₂C(═O)NH₂ H H 2 O45 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 2 O46 a, b, c, or d H CH₂C(═O)OH H 2 O47 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 2 O48 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H2 O49 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 2 O50 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 2 O51 a, b, c, or d H CH₂C(═O)NH₂ H 2 O52 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 2 O53 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 2 O54 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 2 O55 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 2 O56 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 2 O57 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 2 O58 a,b, c, or d H H CH₃ 2 O59 a, b, c, or d CH₂C(═O)OH H CH₃ 2 O60 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 2 O61 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 2 O62 a,b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 2 O63 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 2O64 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 2 O65 a, b, c, or d H CH₂C(═O)OHCH₃ 2 O66 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 O67 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 O68 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 2 O69 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 2 O70 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 2 O71 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 O72a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 2 O73 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 O74 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 2 O75 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 O76 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 O77 a, b, c, or d H H H 3O78 a, b, c, or d CH₂C(═O)OH H H 3 O79 a, b, c, or d CH₂C(═O)OCH₃ H H 3O80 a, b, c, or d CH₂CH₂C(═O)OH H H 3 O81 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 3 O82 a, b, c, or d CH₂C(═O)NH₂ H H 3 O83 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 3 O84 a, b, c, or d H CH₂C(═O)OH H 3 O85 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 3 O86 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H3 O87 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 3 O88 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 3 O89 a, b, c, or d H CH₂C(═O)NH₂ H 3 O90 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 3 O91 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 3 O92 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 3 O93 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 3 O94 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 3 O95 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 3 O96 a,b, c, or d H H CH₃ 3 O97 a, b, c, or d CH₂C(═O)OH H CH₃ 3 O98 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 3 O99 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 3 O100a, b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 3 O101 a, b, c, or d CH₂C(═O)NH₂ HCH₃ 3 O102 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 3 O103 a, b, c, or d HCH₂C(═O)OH CH₃ 3 O104 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 O105 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 O106 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH CH₃ 3 O107 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 3 O108a, b, c, or d H CH₂C(═O)NH₂ CH₃ 3 O109 a, b, c, or d CH₂C(═O)OHCH₂C(═O)NH₂ CH₃ 3 O110 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 O111a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 3 O112 a, b, c, or dCH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 O113 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ CH₃ 3 O114 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 3

TABLE 16

(a)

(b)

(c)

(d)and pharmaceutically acceptable salts or solvates thereof, where:

Compound R^(4a) R^(3a) R^(8a) y P P1 a, b, c, or d H H H 1 P2 a, b, c,or d CH₂C(═O)OH H H 1 P3 a, b, c, or d CH₂C(═O)OCH₃ H H 1 P4 a, b, c, ord CH₂CH₂C(═O)OH H H 1 P5 a, b, c, or d CH₂CH₂C(═O)OCH₃ H H 1 P6 a, b, c,or d CH₂C(═O)NH₂ H H 1 P7 a, b, c, or d CH₂CH₂C(═O)NH₂ H H 1 P8 a, b, c,or d H CH₂C(═O)OH H 1 P9 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH H 1 P10 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H 1 P11 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH H 1 P12 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 1 P13 a, b,c, or d H CH₂C(═O)NH₂ H 1 P14 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 1P15 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 1 P16 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 1 P17 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 1 P18 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 P19 a, b,c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 1 P20 a, b, c, or d H H CH₃ 1 P21a, b, c, or d CH₂C(═O)OH H CH₃ 1 P22 a, b, c, or d CH₂C(═O)OCH₃ H CH₃ 1P23 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 1 P24 a, b, c, or dCH₂CH₂C(═O)OCH₃ H CH₃ 1 P25 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 1 P26 a, b,c, or d CH₂CH₂C(═O)NH₂ H CH₃ 1 P27 a, b, c, or d H CH₂C(═O)OH CH₃ 1 P28a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 P29 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 1 P30 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 1 P31 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 1 P32 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 1 P33 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 P34a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 1 P35 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 1 P36 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 1 P37 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 P38 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 1 P39 a, b, c, or d H H H 2P40 a, b, c, or d CH₂C(═O)OH H H 2 P41 a, b, c, or d CH₂C(═O)OCH₃ H H 2P42 a, b, c, or d CH₂CH₂C(═O)OH H H 2 P43 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 2 P44 a, b, c, or d CH₂C(═O)NH₂ H H 2 P45 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 2 P46 a, b, c, or d H CH₂C(═O)OH H 2 P47 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 2 P48 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H2 P49 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 2 P50 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 2 P51 a, b, c, or d H CH₂C(═O)NH₂ H 2 P52 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 2 P53 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 2 P54 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 2 P55 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 2 P56 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 2 P57 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 2 P58 a,b, c, or d H H CH₃ 2 P59 a, b, c, or d CH₂C(═O)OH H CH₃ 2 P60 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 2 P61 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 2 P62 a,b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 2 P63 a, b, c, or d CH₂C(═O)NH₂ H CH₃ 2P64 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 2 P65 a, b, c, or d H CH₂C(═O)OHCH₃ 2 P66 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 P67 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 2 P68 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OHCH₃ 2 P69 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 2 P70 a, b, c, ord H CH₂C(═O)NH₂ CH₃ 2 P71 a, b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 P72a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 2 P73 a, b, c, or dCH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 2 P74 a, b, c, or d CH₂CH₂C(═O)OCH₃CH₂C(═O)NH₂ CH₃ 2 P75 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 P76 a,b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 2 P77 a, b, c, or d H H H 3P78 a, b, c, or d CH₂C(═O)OH H H 3 P79 a, b, c, or d CH₂C(═O)OCH₃ H H 3P80 a, b, c, or d CH₂CH₂C(═O)OH H H 3 P81 a, b, c, or d CH₂CH₂C(═O)OCH₃H H 3 P82 a, b, c, or d CH₂C(═O)NH₂ H H 3 P83 a, b, c, or dCH₂CH₂C(═O)NH₂ H H 3 P84 a, b, c, or d H CH₂C(═O)OH H 3 P85 a, b, c, ord CH₂C(═O)OH CH₂C(═O)OH H 3 P86 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH H3 P87 a, b, c, or d CH₂C(═O)NH₂ CH₂C(═O)OH H 3 P88 a, b, c, or dCH₂CH₂C(═O)NH₂ CH₂C(═O)OH H 3 P89 a, b, c, or d H CH₂C(═O)NH₂ H 3 P90 a,b, c, or d CH₂C(═O)OH CH₂C(═O)NH₂ H 3 P91 a, b, c, or d CH₂C(═O)OCH₃CH₂C(═O)NH₂ H 3 P92 a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ H 3 P93 a,b, c, or d CH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ H 3 P94 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ H 3 P95 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ H 3 P96 a,b, c, or d H H CH₃ 3 P97 a, b, c, or d CH₂C(═O)OH H CH₃ 3 P98 a, b, c,or d CH₂C(═O)OCH₃ H CH₃ 3 P99 a, b, c, or d CH₂CH₂C(═O)OH H CH₃ 3 P100a, b, c, or d CH₂CH₂C(═O)OCH₃ H CH₃ 3 P101 a, b, c, or d CH₂C(═O)NH₂ HCH₃ 3 P102 a, b, c, or d CH₂CH₂C(═O)NH₂ H CH₃ 3 P103 a, b, c, or d HCH₂C(═O)OH CH₃ 3 P104 a, b, c, or d CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 P105 a,b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)OH CH₃ 3 P106 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)OH CH₃ 3 P107 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)OH CH₃ 3 P108a, b, c, or d H CH₂C(═O)NH₂ CH₃ 3 P109 a, b, c, or d CH₂C(═O)OHCH₂C(═O)NH₂ CH₃ 3 P110 a, b, c, or d CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 P111a, b, c, or d CH₂CH₂C(═O)OH CH₂C(═O)NH₂ CH₃ 3 P112 a, b, c, or dCH₂CH₂C(═O)OCH₃ CH₂C(═O)NH₂ CH₃ 3 P113 a, b, c, or d CH₂C(═O)NH₂CH₂C(═O)NH₂ CH₃ 3 P114 a, b, c, or d CH₂CH₂C(═O)NH₂ CH₂C(═O)NH₂ CH₃ 3

4.2d Substituted Benzimidazole-Type Piperidine Compounds of Formulae(I^(‡)A), (I^(‡)A′), and (I^(‡)A″)

Compounds of formula (I^(‡)A) are herein disclosed:

or a pharmaceutically acceptable salt or solvate thereof where:

the Q_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl;

each R² is independently selected from:

-   -   (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³, —C(═O)OT³,        —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³, —O—S(═O)₂T³,        —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,        —N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³,        —N(T³)C(═O)OT³, and —N(T³)S(═O)₂N(T¹)(T²); and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₆-C₁₀)bicycloalkyl,        —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl,        each of which is unsubstituted or substituted with 1, 2, or 3        independently selected R⁷ groups;

each dashed line denotes the presence or absence of a bond (i.e., when adashed line is present there is a double bond at that position and whena dashed line is absent there is only a single bond at that position),provided that:

-   -   (a) one dashed line must denote the presence of a bond (i.e.,        there is a double bond at that position);    -   (b) when one dashed line denotes the presence of a bond (i.e.,        there is a double bond at that position) then the other dashed        line denotes the absence of a bond (i.e., there is only a single        bond at that other position);    -   (c) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        present (i.e., there is a double bond at that position), then R³        is absent; and    -   (d) when the dashed line within the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring is        absent (i.e., there is only a single bond at that position),        then R³ is present;

R³, when present, is:

-   -   (a) —H; or    -   (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,        2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy,        —N(R⁶)₂, —C(═O)OR⁹, and —C(═O)N(R⁶)₂; or    -   (c) —(C₃-C₇)cycloalkyl which is unsubstituted or substituted        with 1, 2, or 3 groups independently selected from —OH,        —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹, and        —C(═O)N(R⁶)₂;

t is an integer selected from 0, 1, 2, and 3;

when t is 0, the Q_(x) ring is a -(3-, 4-, 5-, 6-, or7-membered)heterocycle containing 1, 2, 3, or 4 ring heteroatomsindependently selected from N,N(R⁴), O, and S wherein said heterocycleis unsubstituted or substituted with (R¹⁰), groups provided that atleast one ring heteroatom is N or N(R⁴) and provided that when thedashed line connecting the Q_(x) ring to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring is present(i.e., there is a double bond at that position), U¹ is C or CH, and

when t is 1, 2, or 3 the Q_(x) ring is a (5- or 6-membered)heterocycleselected from:

each R⁴, when present, is independently selected from:

-   -   (a) —H; and    -   (b) —X, —(C₁-C₆)alkyl-X, -(5- or 6-membered)heterocycle-X, or        -(5- or 6-membered)heterocycle-(C₁-C₆)alkyl-X; and    -   (c) —(CH₂)_(d)—C(═Y)CN, —(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³,        —(CH₂)_(d)—C(═Y)YX, —(CH₂)_(d)—C(═Y)YT³,        —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,        —(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,        —(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,        —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³;        —(CH₂)_(d)—N(R⁹)S(═O)₂T³; or —(CH₂)_(d)—S(═O)₂T⁴; and    -   (d) —[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶,        —[CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—O]_(b)—R¹⁶,        —[CH₂—CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—CH₂—O]_(b)—R¹⁶,        —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—CH₂—O]_(b)—R⁶, or        —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶;

X is selected from:

-   -   (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,        —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and        -(5- or 6-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, or 3 independently selected R⁸ groups;        and    -   (b)-phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each Y is independently O or S;

each R¹⁶ is independently H or CH₃;

s is an integer selected from 0, 1, 2, 3, and 4;

when s is 1, 2, 3, or 4, each R¹⁰ is independently —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²), and when s is 2, 3, or 4, each R¹⁰ isindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²) or two R¹⁰ groupsattached to the same carbon atom and are gem-dimethyl, gem-difluoro, ═O,or ═S;

A and B are independently selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of        which is unsubstituted or substituted with 1 or 2 substituents        independently selected from —OH, —S(═O)₂NH₂, —C(═O)OT³,        —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3 independently        selected -halo; or    -   (c) A-B can together form a (C₂-C₆)bridge, which is        unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7, or 8        substituents independently selected from —OH, —(C₁-C₄)alkyl,        -halo, and —C(halo)₃, and which bridge optionally contains        —HC═CH— or —O— within the (C₂-C₆)bridge; wherein the 5-membered,        nitrogen-containing ring that is fused to the Q_(a) ring can be        in the endo- or exo-configuration with respect to the A-B        bridge;

wherein the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring can be in the endo- or exo-configuration with respect to theA-B bridge;

Z is —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—;

R¹ is selected from:

-   -   (a) —H, -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₆-C₁₄)bicycloalkyl,        —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to        7-membered)heterocycle, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁸ groups;        and    -   (c)

-   -    and    -   (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with 1, 2, 3, or 4 independently selected R⁷ groups;

each R⁵ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃,—NO₂, —CH═N(R⁹), —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH,—N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁶ is independently —H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, ortwo R⁶ groups attached to the same nitrogen atom can together form a-(5- to 8-membered)heterocyclic ring, wherein the number of atoms in thering includes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³);

each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹;

each R⁸ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹;

each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo);

each R¹² is independently —H or —(C₁-C₄)alkyl;

R¹³ is selected from:

-   -   (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂,        —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy, —(C₅-C₁₀)cycloalkenyl, and        -(3- to 7-membered)heterocycle, each of which is unsubstituted        or substituted with 1, 2, 3, or 4 independently selected R⁸        groups; and    -   (c)

-   -    and    -   (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which is        unsubstituted or substituted with 1, 2, or 3 independently        selected R⁷ groups;

each T¹ and T² is independently —H or -(C₁-C₁₀)alkyl which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁵groups and, optionally, in which any -(C₁-C₁₀)alkyl carbon atom exceptthe carbon atom bonded directly to the atom to which T¹ or T² isattached is independently replaced by O, S, or N(R⁶), or T¹ and T² cantogether form a -(5- to 8-membered)heterocyclic ring wherein the numberof atoms in the ring includes the nitrogen atom to which T¹ and T² arebonded, said -(5- to 8-membered)heterocyclic ring is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, any 1 or 2 carbon atoms in said -(5- to8-membered)heterocyclic ring is independently replaced by O, S, orN(R⁶);

each T³ is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T³ is attached isindependently replaced by O, S, or N(R¹²);

each T⁴ is independently a -(5- or 6-membered)heteroaryl which isunsubstituted or substituted with 1 or 2 independently selected R¹²groups;

each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, -phenyl,or -benzyl;

a is an integer selected from 0, 1, and 2;

each b is, independently, an integer selected from 1, 2, 3, 4, 5, and 6;

each d is, independently, an integer selected from 0, 1, 2, and 3;

m is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;

n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9;

e and f are each an integer independently selected from 0, 1, 2, 3, 4,and 5 provided that 2≦(e+f)≦5;

each p is an integer independently selected from 0, 1, 2, 3, and 4; and

each halo is independently —F, —Cl, —Br, or —I.

In one embodiment, the compound of formula (IA) is a compound of formula(I^(‡)A′):

or a pharmaceutically acceptable salt or solvate thereof where R¹, R²,R¹⁰, Q_(a), Q_(x), U¹, U², A, B, Z, a, s, and t are as defined for thecompounds of formula (I^(‡)A).

In another embodiment, the compound of formula (I^(‡)A) is a compound offormula (I^(‡)A″):

or a pharmaceutically acceptable salt or solvate thereof where R¹, R²,R³, R¹⁰, Q_(a), Q_(x), U¹, U², A, B, Z, a, s, and t are as defined forthe compounds of formula (IA).

In another embodiment, t is 1, 2, or 3, s is 0, 1, or 2, and the Q_(x)ring is selected from:

In another embodiment, t is 1, s is 0, 1, or 2, and the Q_(x) ring isselected from:

In another embodiment, t is 1, s is 0, 1, or 2, and the Q_(x) ring isselected from:

In another embodiment, t is 1, s is 0, 1, or 2, and the Q_(x) ring isselected from:

In another embodiment, t is 1 and the Q_(x) ring is selected from:

In another embodiment, t is 1 and the Q_(x) ring is selected from:

In another embodiment, t is 0, s is 0, 1, or 2, and the Q_(x) ring isselected from:

In another embodiment, t is 0, s is 0, 1, or 2, and the Q_(x) ring isselected from:

In another embodiment, t is 0 and the Q_(x) ring is selected from:

In another embodiment, t is 0 and the Q_(x) ring is selected from:

In another embodiment, t is 0 and the Q_(x) ring is selected from:

In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)OH,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)OH,CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl,CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl,C(═O)OH, CH₂NHS(═O)₂(C₁-C₄)alkyl, or CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl.

In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH,CH₂NHS(═O)₂(C₁-C₄)alkyl, or CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)OH, CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), or CH₂C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂C(═O)O—(C₁-C₄)alkyl, CH₂NHS(═O)₂(C₁-C₄)alkyl,CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl, S(═O)₂-4-(3,5-dimethylisoxazole), orCH₂C(═O)OH. In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂C(═O)OH, CH₂NHS(═O)₂(C₁-C₄)alkyl,CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl, or C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),C(═O)O—(C₁-C₄)alkyl, CH₂NHS(═O)₂(C₁-C₄)alkyl,CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl, S(═O)₂-4-(3,5-dimethylisoxazole), orC(═O)OH. In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂NHS(═O)₂(C₁-C₄)alkyl, CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl,S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)NH(C₁-C₄)alkyl, orCH₂C(═O)N[(C₁-C₄)alkyl]₂.

In another embodiment, R⁴ is H, 2-(1H-imidazole),2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,S(═O)₂-4-(3,5-dimethylisoxazole), or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, C(═O)OH, S(═O)₂-4-(3,5-dimethylisoxazole), orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH,S(═O)₂-4-(3,5-dimethylisoxazole), or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,C(═O)O—(C₁-C₄)alkyl, C(═O)OH, S(═O)₂-4-(3,5-dimethylisoxazole), orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)OH,S(═O)₂-4-(3,5-dimethylisoxazole), or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H, 2-(1H-imidazole), 2-(1-methyl-1H-imidazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)OH, S(═O)₂-4-(3,5-dimethylisoxazole)C(═O)O—(C₁-C₄)alkyl, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1H-imidazole), 2-(1-methyl-1H-imidazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl,CH₂CH₂C(═O)OH, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl,C(═O)OH, or S(═O)₂-4-(3,5-dimethylisoxazole).

In another embodiment, R⁴ is H, 2-(1-methyl-1H-imidazole),S(═O)₂-4-(3,5-dimethylisoxazole), CH₂CH₂C(═O)O—(C₁-C₄)alkyl, orCH₂CH₂C(═O)OH. In another embodiment, R⁴ is H,2-(1-methyl-1H-imidazole), S(═O)₂-4-(3,5-dimethylisoxazole),CH₂CH₂C(═O)OH, or CH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ isH, 2-(1-methyl-1H-imidazole), S(═O)₂-4-(3,5-dimethylisoxazole),CH₂C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)OH. In another embodiment, R⁴ is H,2-(1-methyl-1H-imidazole), S(═O)₂-4-(3,5-dimethylisoxazole), CH₂C(═O)OH,or C(═O)O—(C₁-C₄)alkyl. In another embodiment, R⁴ is H,2-(1-methyl-1H-imidazole), S(═O)₂-4-(3,5-dimethylisoxazole),C(═O)O—(C₁-C₄)alkyl, or C(═O)OH. In another embodiment, R⁴ is H,2-(1-methyl-1H-imidazole), S(═O)₂-4-(3,5-dimethylisoxazole),CH₂CH₂C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, R⁴ is H, CH₂NHS(═O)₂(C₁-C₄)alkyl,CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl, or S(═O)₂-4-(3,5-dimethylisoxazole). Inanother embodiment, R⁴ is H, CH₂NHS(═O)₂(C₁-C₄)alkyl, orS(═O)₂-4-(3,5-dimethylisoxazole). In another embodiment, R⁴ is H,CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl, or S(═O)₂-4-(3,5-dimethylisoxazole). Inanother embodiment, R⁴ is CH₂NHS(═O)₂(C₁-C₄)alkyl,CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl, or S(═O)₂-4-(3,5-dimethylisoxazole). Inanother embodiment, R⁴ is CH₂NHS(═O)₂(C₁-C₄)alkyl orS(═O)₂-4-(3,5-dimethylisoxazole). In another embodiment, R⁴ isCH₂CH₂NHS(═O)₂(C₁-C₄)alkyl or S(═O)₂-4-(3,5-dimethylisoxazole). Inanother embodiment, R⁴ is H or CH₂NHS(═O)₂(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H or CH₂CH₂NHS(═O)₂(C₁-C₄)alkyl. In anotherembodiment, R⁴ is H or S(═O)₂-4-(3,5-dimethylisoxazole). In anotherembodiment, R⁴ is CH₂NHS(═O)₂(C₁-C₄)alkyl. In another embodiment, R⁴ isCH₂CH₂NHS(═O)₂(C₁-C₄)alkyl. In another embodiment, R⁴ isS(═O)₂-4-(3,5-dimethylisoxazole).

In another embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, OCH₃, OCH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ is CH₃,CH₂CH₃, OCH₃, OCH₂CH₃, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ is CH₃,CH₂CH₃, OCH₃, OCH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ is CH₃,CH₂CH₃, OCH₃, OCH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, sis 1 and R¹⁰ is CH₃, CH₂CH₃, OCH₃, OCH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl,CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, or C(═O)OH.

In another embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, OCH₃, OCH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, OCH₃, OCH₂CH₃, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In another embodiment, s is 1 and R¹⁰ isCH₃, CH₂CH₃, OCH₃, OCH₂CH₃, C(═O)OH or CH₂C(═O)NH(C₁-C₄)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, OCH₃, OCH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, OCH₃, OCH₂CH₃,CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. Inanother embodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, OCH₃, OCH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₄)alkyl. In anotherembodiment, s is 1 and R¹⁰ is CH₃, CH₂CH₃, OCH₃, OCH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, is 1 and R¹⁰ is CH₃,CH₂CH₃, OCH₃, OCH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, or C(═O)OH.

In another embodiment, s is 1 and R¹⁰ is CH₃, OCH₃,CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, s is 1 and R¹⁰ is CH₃, OCH₃, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkylor C(═O)OH. In another embodiment, s is 1 and R¹⁰ is CH₃, OCH₃, C(═O)OHor CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 1 and R¹⁰ is CH₃,OCH₃, CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 1 and R¹⁰ is OCH₃. In another embodiment, sis 1 and R¹⁰ is OCH₂CH₃.

In another embodiment, s is 2 and each R¹⁰ is, independently, OCH₃,OCH₂CH₃, CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl,C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 2 andeach R¹⁰ is, independently, OCH₃, OCH₂CH₃, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently, OCH₃, OCH₂CH₃,CH₂C(═O)O—(C₁-C₆)alkyl, C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently, OCH₃, OCH₂CH₃,CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, orCH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, OCH₃, OCH₂CH₃, CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₆)alkyl, or C(═O)OH.

In another embodiment, s is 2 and each R¹⁰ is, independently, OCH₃,OCH₂CH₃, CH₂C(═O)O—(C₁-C₆)alkyl, CH₂C(═O)OH, or C(═O)O—(C₁-C₆)alkyl. Inanother embodiment, s is 2 and each R¹⁰ is, independently, OCH₃,OCH₂CH₃, CH₂C(═O)OH, C(═O)O—(C₁-C₆)alkyl, or C(═O)OH. In anotherembodiment, s is 2 and each R¹⁰ is, independently, OCH₃, OCH₂CH₃,C(═O)OH, or CH₂C(═O)NH(C₁-C₆)alkyl. In another embodiment, s is 2 andeach R¹⁰ is, independently, OCH₃, OCH₂CH₃, CH₂C(═O)O—(C₁-C₆)alkyl, orCH₂C(═O)NH(C₁-C₆)alkyl.

In another embodiment, s is 2 and each R¹⁰ is, independently, OCH₃,OCH₂CH₃, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, OCH₃, OCH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, C(═O)OH, orCH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, OCH₃, OCH₂CH₃, CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl, or CH₂C(═O)NH(C₁-C₄)alkyl. In another embodiment, sis 2 and each R¹⁰ is, independently, OCH₃, OCH₂CH₃,CH₂C(═O)O—(C₁-C₄)alkyl, CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl, or C(═O)OH.

In another embodiment, s is 2 and each R¹⁰ is, independently, OCH₃,CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)OH, C(═O)O—(C₁-C₄)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently, OCH₃, CH₂C(═O)OH,C(═O)O—(C₁-C₄)alkyl or C(═O)OH. In another embodiment, s is 2 and eachR¹⁰ is, independently, OCH₃, C(═O)OH or CH₂C(═O)NH(C₁-C₄)alkyl. Inanother embodiment, s is 2 and each R¹⁰ is, independently, OCH₃,CH₂C(═O)O—(C₁-C₄)alkyl or CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₆)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, CH₂C(═O)OH. In another embodiment, s is 2 and each R¹⁰is, independently, C(═O)O—(C₁-C₆)alkyl. In another embodiment, s is 2and each R¹⁰ is, independently, C(═O)OH. In another embodiment, s is 2and each R¹⁰ is, independently, CH₂C(═O)NH(C₁-C₆)alkyl. In anotherembodiment, s is 2 and each R¹⁰ is, independently,CH₂C(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 2 and each R¹⁰ is,independently, C(═O)O—(C₁-C₄)alkyl. In another embodiment, s is 1 andR¹⁰ is CH₂C(═O)NH(C₁-C₄)alkyl.

In another embodiment, s is 3. In another embodiment, s is 3, two R¹⁰groups are gem-dimethyl, gem-difluoro, or ═O, and the other R¹⁰ group is—F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²). In another embodiment, s is 3, two R¹⁰ groupsare gem-dimethyl, gem-difluoro, or ═S, and the other R¹⁰ group is —F,—Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²). In another embodiment, s is 3, two R¹⁰ groupsare gem-dimethyl, ═S, or ═O, and the other R¹⁰ group is —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²). In another embodiment, s is 3, two R¹⁰ groupsare gem-difluoro, ═S, or ═O, and the other R¹⁰ group is —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²). In another embodiment, s is 3, two R¹⁰ groupsare gem-dimethyl or ═O, and the other R¹⁰ group is —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²). In another embodiment, s is 3, two R¹⁰ groupsare gem-difluoro or ═O, and the other R¹⁰ group is —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, or —OCH₂CH₃. In another embodiment, s is 3, two R¹⁰groups are gem-dimethyl, gem-difluoro, or ═O, and the other R¹⁰ group is—F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃. In another embodiment, s is3, two R¹⁰ groups are gem-dimethyl, gem-difluoro, or ═S, and the otherR¹⁰ group is —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃. In anotherembodiment, s is 3, two R¹⁰ groups are gem-dimethyl, ═S, or ═O, and theother R¹⁰ group is —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃. Inanother embodiment, s is 3, two R¹⁰ groups are gem-difluoro, ═S, or ═O,and the other R¹⁰ group is —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃.In another embodiment, s is 3, two R¹⁰ groups are gem-dimethyl or ═O,and the other R¹⁰ group is —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃.In another embodiment, s is 3, two R¹⁰ groups are gem-difluoro or ═O,and the other R¹⁰ group is —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃.

In another embodiment, s is 4. In another embodiment, s is 4, two R¹⁰groups are gem-dimethyl, gem-difluoro, or ═O, and the other two R¹⁰groups are independently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²). In anotherembodiment, s is 4, two R¹⁰ groups are gem-dimethyl, gem-difluoro, or═S, and the other two R¹⁰ groups are independently —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, —OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or—(CH₂)_(d)—C(═Y)N(T¹)(T²). In another embodiment, s is 4, two R¹⁰ groupsare gem-dimethyl, ═S, or ═O, and the other two R¹⁰ groups areindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, —OCH₂CH₃,—(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²). In anotherembodiment, s is 4, two R¹⁰ groups are gem-difluoro, ═S, or ═O, and theother two R¹⁰ groups are independently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃,—OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²). In anotherembodiment, s is 4, two R¹⁰ groups are gem-dimethyl or ═O, and the othertwo R¹⁰ groups are independently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃,—OCH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²). In anotherembodiment, s is 4, two R¹⁰ groups are gem-difluoro or ═O, and the othertwo R¹⁰ groups are independently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or—OCH₂CH₃. In another embodiment, s is 4, two R¹⁰ groups aregem-dimethyl, gem-difluoro, or ═O, and the other two R¹⁰ groups areindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃. In anotherembodiment, s is 4, two R¹⁰ groups are gem-dimethyl, gem-difluoro, or═S, and the other two R¹⁰ groups are independently —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, or —OCH₂CH₃. In another embodiment, s is 4, two R¹¹groups are gem-dimethyl, ═S, or ═O, and the other two R¹⁰ groups areindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃. In anotherembodiment, s is 4, two R¹⁰ groups are gem-difluoro, ═S, or ═O, and theother two R¹⁰ groups are independently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or—OCH₂CH₃. In another embodiment, s is 4, two R¹⁰ groups are gem-dimethylor ═O, and the other two R¹⁰ groups are independently —F, —Cl, —CH₃,—CH₂CH₃, —OCH₃, or —OCH₂CH₃. In another embodiment, s is 4, two R¹⁰groups are gem-difluoro or ═O, and the other two R¹⁰ groups areindependently —F, —Cl, —CH₃, —CH₂CH₃, —OCH₃, or —OCH₂CH₃.

In another embodiment, s is 4, two R¹⁰ groups are gem-dimethyl,gem-difluoro, or ═O, and the other two R¹⁰ groups are gem-dimethyl,gem-difluoro, or ═O. In another embodiment, s is 4, two R¹⁰ groups aregem-dimethyl, gem-difluoro, or ═O, and the other two R¹⁰ groups aregem-dimethyl, gem-difluoro, or ═S. In another embodiment, s is 4, twoR¹⁰ groups are gem-dimethyl, gem-difluoro, or ═S, and the other two R¹⁰groups are gem-dimethyl, gem-difluoro, or ═S. In another embodiment, sis 4, two R¹⁰ groups are gem-dimethyl or ═O, and the other two R¹⁰groups are gem-dimethyl or ═O. In another embodiment, s is 4, two R¹⁰groups are gem-difluoro or ═O, and the other two R¹⁰ groups aregem-difluoro or ═O. In another embodiment, s is 4, two R¹⁰ groups aregem-dimethyl or ═O, and the other two R¹⁰ groups are gem-difluoro, or═O. In another embodiment, s is 4, two R¹⁰ groups are gem-dimethyl, andthe other two R¹⁰ groups are gem-dimethyl, gem-difluoro, or ═O. Inanother embodiment, s is 4, two R¹⁰ groups are gem-difluoro, and theother two R¹⁰ groups are gem-dimethyl, gem-difluoro, or ═O. In anotherembodiment, s is 4, two R¹⁰ groups are ═O, and the other two R¹⁰ groupsare gem-dimethyl, gem-difluoro, or ═O. In another embodiment, s is 4,two R¹⁰ groups are ═O, and the other two R¹⁰ groups are gem-dimethy or═O. In another embodiment, s is 4, two R¹⁰ groups are ═O, and the othertwo R¹⁰ groups are gem-difluoro or ═O. In another embodiment, s is 4,two R¹⁰ groups are ═O, and the other two R¹⁰ groups are ═O. In anotherembodiment, s is 4, two R¹⁰ groups are ═S, and the other two R¹⁰ groupsare ═S.

In another embodiment, T⁴ is a -(5-membered)heteroaryl which isunsubstituted or substituted with 1 or 2 independently selected R¹²groups. In another embodiment, T⁴ is a -(5-membered)heteroaryl which isunsubstituted. In another embodiment, T⁴ is a -(5-membered)heteroarylwhich is substituted with 1 or 2 independently selected R¹² groups. Inanother embodiment, T⁴ is a -(5-membered)heteroaryl which is substitutedwith 1 R¹² group. In another embodiment, T⁴ is a -(5-membered)heteroarylwhich is substituted with 2 independently selected R¹² groups. Inanother embodiment, T⁴ is a -(6-membered)heteroaryl which isunsubstituted or substituted with 1 or 2 independently selected R¹²groups. In another embodiment, T⁴ is a -(6-membered)heteroaryl which isunsubstituted. In another embodiment, T⁴ is a -(6-membered)heteroarylwhich is substituted with 1 or 2 independently selected R¹² groups. Inanother embodiment, T⁴ is a -(6-membered)heteroaryl which is substitutedwith 1 R¹² group. In another embodiment, T⁴ is a -(6-membered)heteroarylwhich is substituted with 2 independently selected R¹² groups.

In another embodiment, T⁴ is furyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, 1,2,3thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, or thiophenylwhich is unsubstituted or substituted with 1 or 2 independently selectedR¹² groups. In another embodiment, T⁴ is furyl, pyrrolyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5 oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, 1,2,3thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, or thiophenylwhich is unsubstituted. In another embodiment, T⁴ is furyl, pyrrolyl,oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5 oxadiazolyl, 1,2,3-triazolyl, pyrazolyl,isothiazolyl, 1,2,3 thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, or thiophenyl which is substituted with 1 or 2independently selected R¹² groups. In another embodiment, T⁴ is furyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5 oxadiazolyl,1,2,3-triazolyl, pyrazolyl, isothiazolyl, 1,2,3 thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, or thiophenyl which issubstituted with 1 R¹² group. In another embodiment, T⁴ is furyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5 oxadiazolyl,1,2,3-triazolyl, pyrazolyl, isothiazolyl, 1,2,3 thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, or thiophenyl which issubstituted with 2 independently selected R¹² groups.

In another embodiment, T⁴ is furyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, isoxazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, orthiophenyl which is unsubstituted or substituted with 1 or 2independently selected R¹² groups. In another embodiment, T⁴ is furyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl,pyrazolyl, isothiazolyl, or thiophenyl which is unsubstituted. Inanother embodiment, T⁴ is furyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, isoxazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, orthiophenyl which is substituted with 1 or 2 independently selected R¹²groups. In another embodiment, T⁴ is furyl, pyrrolyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, pyrazolyl,isothiazolyl, or thiophenyl which is substituted with 1 R¹² group. Inanother embodiment, T⁴ is furyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, isoxazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl, orthiophenyl which is substituted with 2 independently selected R¹²groups.

In another embodiment, T⁴ is oxazolyl, imidazolyl, isoxazolyl,1,2,3-triazolyl, or pyrazolyl which is unsubstituted or substituted with1 or 2 independently selected R¹² groups. In another embodiment, T⁴ isoxazolyl, imidazolyl, isoxazolyl, 1,2,3-triazolyl, or pyrazolyl which isunsubstituted. In another embodiment, T⁴ is oxazolyl, imidazolyl,isoxazolyl, 1,2,3-triazolyl, or pyrazolyl which is substituted with 1 or2 independently selected R¹² groups. In another embodiment, T⁴ isoxazolyl, imidazolyl, isoxazolyl, 1,2,3-triazolyl, or pyrazolyl which issubstituted with 1 R¹² group. In another embodiment, T⁴ is oxazolyl,imidazolyl, isoxazolyl, 1,2,3-triazolyl, or pyrazolyl which issubstituted with 2 independently selected R¹² groups.

In one embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid. In another embodiment, the Substituted Benzimidazole-TypePiperidine Compound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]midazol-2-yl)pyrimidine-2,4(1H,3H)-dione.

In one embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid or1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid or1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid or(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazoleor1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazoleor(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazoleor6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazoleor(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazoleor6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane)or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.

In one embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,or1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,or(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,or(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]midazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,or(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).

In one embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,or(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).In another embodiment, the Substituted Benzimidazole-Type PiperidineCompound is not1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),or6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.

Each and every embodiment set forth in Sections 4.1, 4.2a, and 4.2brelating to the piperidine ring and the A, B, Z, and R¹ substituentsthereto, and to the Q_(a), Q_(x), R², R³, R⁴, R¹⁰, a, s, and t variablegroups referenced therein also relate to the SubstitutedBenzimidazole-Type Piperidine Compounds in this section; therefore,those embodiments are not repeated here but are instead incorporated byreference in their entirety.

4.3a Substituted Benzimidazole-Type Piperidine Compounds of Formulae(IB), (IB′), and (IB″)

As stated above, the disclosure encompasses SubstitutedBenzimidazole-Type Piperidine Compounds of Formula (IB):

or a pharmaceutically acceptable derivative thereof where each dashedline, Q_(a), R¹, R², R³, R¹⁵, A, B, W, Z, and a are defined above forthe Substituted Benzimidazole-Type Piperidine Compounds of Formula (IB).

In one embodiment, the compound of formula (IB) is a compound of formula(IB′):

or a pharmaceutically acceptable salt or solvate thereof where —W— is asingle bond, —CH₂—, —NH—, —O—, —CH₂—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,—CH₂—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,—O—(C₁-C₃)alkylene-N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—, —CH₂—O—, or—CH₂—O—(C₁-C₃)alkylene- and Q_(a), R¹, R², R¹¹, R¹⁵, A, B, Z, and a areas defined for the compounds of formula (IB).

In another embodiment, the compound of formula (IB) is a compound offormula (IB″):

or a pharmaceutically acceptable salt or solvate thereof where ═W— is adouble bond, ═CH—, ═N—, ═CH—(C₁-C₃)alkylene-, ═N—(C₁-C₃)alkylene-,═CH—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-,═CH—(C₁-C₃)alkylene-N(R¹¹)—, ═N—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—,═CH—O—, OR═CH—O—(C₁-C₃)alkylene- and Q_(a), R¹, R², R³, R¹¹, R¹⁵, A, B,Z, and a are as defined for the compounds of formula (IB).

In another embodiment, ═W— is a single bond, double bond, —CH₂—, ═N—,—CH═N—, or —NH—. In another embodiment, ═W— is a single bond, doublebond, —CH₂—, ═N—, or —CH═N—. In another embodiment, ═W— is a singlebond, double bond, —CH₂—, ═N—, or —NH—. In another embodiment, ═W— is asingle bond, double bond, —CH₂—, —CH═N—, or —NH—. In another embodiment,═W— is a single bond, double bond, ═N—, —CH═N—, or —NH—. In anotherembodiment, ═W— is a single bond, —CH₂—, ═N—, —CH═N—, or —NH—. Inanother embodiment, ═W— is a double bond, —CH₂—, ═N—, —CH═N—, or —NH—.In another embodiment, ═W— is —CH₂—, ═N—, —CH═N—, or —NH—. In anotherembodiment, ═W— is a single bond or a double bond. In anotherembodiment, ═W— is a single bond or —NH—. In another embodiment, ═W— isa double bond or —CH₂—. In another embodiment, ═W— is a —CH₂— or ═N—. Inanother embodiment, ═W— is a ═N— or —CH═N—. In another embodiment, ═W—is —CH═N— or —NH—. In another embodiment, ═W— is a single bond. Inanother embodiment, ═W— is a double bond. In another embodiment, ═W— is—CH₂—. In another embodiment, ═W— is ═N—. In another embodiment, ═W— is—CH═N—. In another embodiment, ═W— is —NH—.

In another embodiment, R¹⁵ is —OH, —C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅,—C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment,R¹⁵ is —C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, R¹⁵ is—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂,—CH₂C(═O)OH, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or—C(═NH)NHOCH₃.

In another embodiment, ═W— is —CH₂—, ═N—, —CH═N—, or —NH— and R¹⁵ is—OH, —C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂—,═N—, —CH═N—, or —NH— and R¹⁵ is —C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅,—C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment,═W— is —CH₂—, ═N—, —CH═N—, or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅,—C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment,═W— is —CH₂—, ═N—, —CH═N—, or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂,—CH₂C(═O)OH, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or—C(═NH)NHOCH₃.

In another embodiment, ═W— is —CH₂— or ═N— and R¹⁵ is —OH, —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or ═N— and R¹⁵ is—C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or═N— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or═N— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is —CH₂— or —CH═N— and R¹⁵ is —OH, —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or —CH═N— and R¹⁵ is—C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or—CH═N— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or—CH═N— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is —CH₂— or —NH— and R¹⁵ is —OH, —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or —NH— and R¹⁵ is—C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or—NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— or—NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is ═N— or —CH═N— and R¹⁵ is —OH, —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is ═N— or —CH═N— and R¹⁵ is—C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is ═N— or—CH═N— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is ═N— or—CH═N— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is ═N— or —NH— and R¹⁵ is —OH, —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is ═N— or —NH— and R¹⁵ is—C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is ═N— or—NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is ═N— or—NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is —CH═N— or —NH— and R¹⁵ is —OH, —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH═N— or —NH— and R¹⁵ is—C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH═N—or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH═N—or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is —CH₂— and R¹⁵ is —OH, —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— and R¹⁵ is —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— and R¹⁵ is—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH₂— and R¹⁵ is—C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is ═N— and R¹⁵ is —OH, —C(═O)OH, —C(═O)OCH₃,—C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅,—C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In anotherembodiment, ═W— is ═N— and

R¹⁵ is —C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is ═N— andR¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is ═N— and R¹⁵ is —C(═O)OCH₃,—C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OCH₂C(═O)OH,—C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is —CH═N— and R¹⁵ is —OH, —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH═N— and R¹⁵ is—C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH═N—and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —CH═N—and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, ═W— is —NH— and R¹⁵ is —OH, —C(═O)OH, —C(═O)OCH₃,—C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅,—C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In anotherembodiment, ═W— is —NH— and R¹⁵ is —C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅,—C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment,═W— is —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH,—CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH,—OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅,—C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅. In another embodiment, ═W— is —NH— andR¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.

In another embodiment, when ═W— is a single bond and R¹⁵ is (C₁)alkyl,R⁸ is not ═O or ═S. In another embodiment, when ═W— is a single bond andR¹⁵ is (C₁)alkyl, R⁸ is not —OH or —SH. In another embodiment, when ═W—is a single bond and R¹⁵ is (C₁)alkyl, R⁸ is not halo. In anotherembodiment, when ═W— is a single bond and R¹⁵ is (C₁)alkyl, R⁸ is not═O, ═S, —OH, or —SH. In another embodiment, when ═W— is a single bondand R¹⁵ is (C₁)alkyl, R⁸ is not ═O, ═S, or halo. In another embodiment,when ═W— is a single bond and R¹⁵ is (C₁)alkyl, R⁸ is not —OH, —SH, orhalo. In another embodiment, when ═W— is a single bond and R¹⁵ is(C₁)alkyl, R⁸ is not ═O, ═S, —OH, —SH, or halo.

Each and every embodiment set forth in Sections 4.1, 4.2a, 4.2b, and4.2d relating to the piperidine ring and the A, B, Z, and R¹substituents thereto, and to the Q_(a), R², R³, R¹¹, and a variablegroups referenced therein also relate to the SubstitutedBenzimidazole-Type Piperidine Compounds in this section; therefore,those embodiments are not repeated here but are instead incorporated byreference in their entirety.

4.3b Substituted Benzimidazole-Type Piperidine Compounds of Formulae(IB), (IB′), and (IB″)

In another embodiment, R¹⁵, when present, is selected from:

-   -   (a) —H; and    -   (b) —(C₁-C₂)alkyl which is substituted with 1, 2, or 3        independently selected R⁸ groups; and    -   (c) —(C₃-C₄)alkyl and —O—(C₁-C₄)alkyl, each of which is        unsubstituted or substituted with 1, 2, 3, or 4 independently        selected R⁸ groups;    -   (d) provided that when        is a single bond, a double bond, or —O—, R¹⁵ is not —H.

In another embodiment, each R⁸ is independently —(C₁-C₄)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or 6-membered)heteroaryl,—(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, ═N(R⁹), —N₃, —NO₂,—CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹²,—N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹,—C(═O)N(T¹)(T²), —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, or —S(═O)R⁹.

In another embodiment, R¹¹ is —H or —(C₁-C₄)alkyl which is substitutedwith —OH or —(C₁-C₄)alkoxy. In another embodiment, R¹¹ is —H or—(C₁-C₄)alkyl which is substituted with —OH. In another embodiment, R¹¹is —H or —(C₁-C₄)alkyl which is substituted with —(C₁-C₄)alkoxy. Inanother embodiment, R¹¹ is —H or —CH₃ which is substituted with —OH or—(C₁-C₄)alkoxy. In another embodiment, R¹¹ is —H or —CH₃ which issubstituted with —OH. In another embodiment, R¹¹ is —H or —CH₃ which issubstituted with —(C₁-C₄)alkoxy. In another embodiment, R¹¹ is —H or—CH₂CH₃ which is substituted with —OH or —(C₁-C₄)alkoxy. In anotherembodiment, R¹¹ is —H or —CH₂CH₃ which is substituted with —OH. Inanother embodiment, R¹¹ is —H or —CH₂CH₃ which is substituted with—(C₁-C₄)alkoxy. In another embodiment, R¹¹ is —H or —CH(CH₃)₂ which issubstituted with —OH or —(C₁-C₄)alkoxy. In another embodiment, R¹ is —Hor —CH(CH₃)₂ which is substituted with —OH. In another embodiment, R¹¹is —H or —CH(CH₃)₂ which is substituted with —(C₁-C₄)alkoxy. In anotherembodiment, R¹¹ is —H or —(C₁-C₄)alkyl which is unsubstituted. Inanother embodiment, R¹¹ is —H or —CH₃. In another embodiment, R¹¹ is —Hor —CH₂CH₃. In another embodiment, R¹¹ is —H or —CH(CH₃)₂. In anotherembodiment, R¹ is —CH₃. In another embodiment, R¹¹ is —CH₂CH₃. Inanother embodiment, R¹¹ is —CH(CH₃)₂.

Each and every embodiment set forth in Sections 4.1, 4.2a, 4.2b, 4.2d,and 4.3a relating to the piperidine ring and the A, B, Z, and R¹substituents thereto, and to the W, Q_(a), R², R³, R¹¹, R¹⁵, and avariable groups referenced therein also relate to the SubstitutedBenzimidazole-Type Piperidine Compounds in this section; therefore,those embodiments are not repeated here but are instead incorporated byreference in their entirety.

4.3c Substituted Benzimidazole-Type Piperidine Compounds of Formula (IB)

In other embodiments, the Substituted Benzimidazole-Type PiperidineCompound of Formula (IB) has one of the formulae of Table 17.

TABLE 17 Formula Compound IBA

IBB

IBC

IBD

IBD₁ ^(†)

IBD₂ ^(‡)

IBE

IBE₁ ^(†)

IBE₂ ^(‡)

IBF

IBF₁ ^(†)

IBF₂ ^(‡)

IBG

IBG₁ ^(†)

IBG₂ ^(‡)

IBH

IBH₁ ^(†)

IBH₂ ^(‡)

IBJ

IBJ₁ ^(†)

IBJ₂ ^(‡)

IBK

IBK₁ ^(†)

IBK₂ ^(‡)

IBL

IBL₁ ^(†)

IBL₂ ^(‡)

IBM

IBM₁ ^(†)

IBM₂ ^(‡)

^(†)indicates the 5-membered, nitrogen-containing ring that is fused tothe benzo or pyridino is in the endo-configuration with respect to thealkyl or —CH₂—O—CH₂— bridge. ^(‡)indicates the 5-membered,nitrogen-containing ring that is fused to the benzo or pyridino is inthe exo-configuration with respect to the alkyl or —CH₂—O—CH₂— bridge.where R¹, R², R¹¹, R¹⁵, Z, and a are as defined above for theSubstituted Benzimidazole-Type Piperidine Compounds of Formula (IB) and—W— is a single bond, —CH₂—, —NH—, —O—, —CH₂—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, —CH₂—(C₂-C₃)alkenylene-,—NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,—O—(C₁-C₃)alkylene-N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—, —CH₂—O—, or—CH₂—O—(C₁-C₃)alkylene-.

4.4 DEFINITIONS

As used in connection with the Substituted Benzimidazole-Type PiperidineCompounds herein, the terms used herein have the following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.Representative straight chain —(C₁-C₁₀)alkyls include -methyl, -ethyl,-n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl,and -n-decyl. A branched alkyl means that one or more straight chain-(C₁-C₈)alkyl groups, such as methyl, ethyl or propyl, replace one orboth hydrogens in a —CH₂— group of a straight chain alkyl. A branchednon-cyclic hydrocarbon means that one or more straight chain—(C₁-C₁₀)alkyl groups, such as methyl, ethyl or propyl, replace one orboth hydrogens in a —CH₂— group of a straight chain non-cyclichydrocarbon. Representative branched -(C₅-C₁₀)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,2-dimethylhexyl,1,3-dimethylhexyl, 3,3-dimethylhexyl, 1,2-dimethylheptyl,1,3-dimethylheptyl, and 3,3-dimethylheptyl.

In connection with the Z group, “—(C₁-C₁₀)alkylene-” means a straightchain or branched non-cyclic hydrocarbon moiety having 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 carbon atoms where two hydrogen atoms on the same or adifferent carbon atom of the moiety are each figuratively removed andreplaced by a bond to one of the two adjoining groups. Representative—(C₁-C₁₀)alkylene-moieties include meth-1,1-diyl, eth-1,1-diyl,eth-1,2-diyl, n-prop-1,1-diyl, n-prop-1,2-diyl, n-prop-1,3-diyl,n-but-1,1-diyl, n-but-1,2-diyl, n-but-1,3-diyl, n-but-1,4-diyl,iso-but-1,1-diyl, iso-but-1,2-diyl, iso-but-1,3-diyl, n-deca-1,1-diyl,n-deca-1,2-diyl, n-deca-1,3-diyl, n-deca-1,4-diyl, n-deca-1,5-diyl,n-deca-1,6-diyl, n-deca-1,7-diyl, n-deca-1,8-diyl, n-deca-1,9-diyl,n-deca-1,10-diyl, and the like.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having 1, 2, 3, 4, 5, or 6 carbon atoms. Representativestraight chain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl,-n-butyl, -n-pentyl, and -n-hexyl. Representative branched—(C₁-C₆)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl,-iso-pentyl, -neopentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

In connection with the Z group, “—(C₁-C₆)alkylene-” means a straightchain or branched non-cyclic hydrocarbon moiety having 1, 2, 3, 4, 5, or6 carbon atoms where two hydrogen atoms on the same or a differentcarbon atom of the moiety are each figuratively removed and replaced bya bond to one of the two adjoining groups. Representative—(C₁-C₆)alkylene-moieties include meth-1,1-diyl, eth-1,1-diyl,eth-1,2-diyl, n-prop-1,1-diyl, n-prop-1,2-diyl, n-prop-1,3-diyl,n-but-1,1-diyl, n-but-1,2-diyl, n-but-1,3-diyl, n-but-1,4-diyl,iso-but-1,1-diyl, iso-but-1,2-diyl, iso-but-1,3-diyl, and the like.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having 1, 2, 3, or 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, and -tert-butyl.

“—(C₃-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having 3 or 4 carbon atoms. Representative straight chain—(C₃-C₄)alkyls include -n-propyl and -n-butyl. Representative branched—(C₃-C₄)alkyls include -iso-propyl, -sec-butyl, -iso-butyl, and-tert-butyl.

In connection with the Z group, “—(C₁-C₄)alkylene-” means a straightchain or branched non-cyclic hydrocarbon moiety having 1, 2, 3, or 4carbon atoms where two hydrogen atoms on the same or a different carbonatom of the moiety are each figuratively removed and replaced by a bondto one of the two adjoining groups. Representative—(C₁-C₄)alkylene-moieties include meth-1,1-diyl, eth-1,1-diyl,eth-1,2-diyl, n-prop-1,1-diyl, n-prop-1,2-diyl, n-prop-1,3-diyl,n-but-1,2-diyl, n-but-1,3-diyl, n-but-1,4-diyl, and the like.

“—(C₁-C₃)alkyl” means a straight chain or branched non-cyclichydrocarbon having 1, 2, or 3 carbon atoms. Representative straightchain —(C₁-C₃)alkyls include -methyl, -ethyl, -n-propyl. Representativebranched —(C₁-C₃)alkyls include -iso-propyl.

In connection with the Z group and the

group, “—(C₁-C₃)alkylene-” means a straight chain or branched non-cyclichydrocarbon moiety having 1, 2, or 3 carbon atoms where two hydrogenatoms on the same or a different carbon atom of the moiety are eachfiguratively removed and replaced by a bond to one of the two adjoininggroups. Representative —(C₁-C₃)alkylene-moieties include meth-1,1-diyl,eth-1,1-diyl, eth-1,2-diyl, n-prop-1,1-diyl, n-prop-1,2-diyl,n-prop-1,3-diyl, and the like.

“—(C₁-C₂)alkyl” means a straight chain non-cyclic hydrocarbon having 1or 2 carbon atoms. Representative —(C₁-C₂)alkyls include -methyl and-ethyl.

In connection with the Z group, “—(C₁-C₂)alkylene-” means a straightchain non-cyclic hydrocarbon moiety having 1 or 2 carbon atoms where twohydrogen atoms on the same or a different carbon atom of the moiety areeach figuratively removed and replaced by a bond to one of the twoadjoining groups. Representative —(C₁-C₂)alkylene-moieties includemeth-1,1-diyl, eth-1,1-diyl, and eth-1,2-diyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms andincluding at least one carbon-carbon double bond. A branched alkenylmeans that one or more straight chain —(C₁-C₈)alkyl groups, such asmethyl, ethyl or propyl, replace one or both hydrogens in a —CH₂— or—CH═ group of a straight chain alkenyl. Representative straight chainand branched (C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl,-2-butenyl, -iso-butylenyl, -1-pentenyl, -2-pentenyl,-3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl,-1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl,-3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl,-3-nonenyl, -1-decenyl, -2-decenyl, -3-decenyl, and the like.

In connection with the Z group, “—(C₂-C₁₀)alkenylene-” means a straightchain or branched non-cyclic hydrocarbon moiety having 2, 3, 4, 5, 6, 7,8, 9, or 10 carbon atoms and including at least one carbon-carbon doublebond where two hydrogen atoms on the same or a different carbon atom ofthe moiety are each figuratively removed and replaced by a bond to oneof the two adjoining groups. Representative —(C₂-C₁₀)alkenylene-moietiesinclude vin-1,1-diyl, vin-1,2-diyl, prop-1-en-1,1-diyl,prop-1-en-1,2-diyl, prop-1-en-1,3-diyl, prop-2-en-1,1-diyl,prop-2-en-1,3-diyl, 2-methylprop-1-en-3,3-diyl, but-2-en-1,1-diyl,but-1-en-4,4-diyl, but-1-en-1,4-diyl, but-2-en-1,4-diyl,but-3-en-1,4-diyl, but-1-en-1,3-diyl, and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having 2, 3, 4, 5, or 6 carbon atoms and including at leastone carbon-carbon double bond. Representative straight chain andbranched (C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, and the like.

In connection with the Z group, “—(C₂-C₆)alkenylene-” means a straightchain or branched non-cyclic hydrocarbon moiety having 2, 3, 4, 5, or 6carbon atoms and including at least one carbon-carbon double bond wheretwo hydrogen atoms on the same or a different carbon atom of the moietyare each figuratively removed and replaced by a bond to one of the twoadjoining groups. Representative —(C₂-C₆)alkenylene-moieties includevin-1,1-diyl, vin-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl,prop-1-en-1,3-diyl, prop-2-en-1,1-diyl, prop-2-en-1,3-diyl,2-methylprop-1-en-3,3-diyl, but-2-en-1,1-diyl, but-1-en-4,4-diyl,but-1-en-1,4-diyl, but-2-en-1,4-diyl, but-3-en-1,4-diyl,but-1-en-1,3-diyl, and the like.

“—(C₂-C₃)alkenyl” means a straight chain non-cyclic hydrocarbon having 2or 3 carbon atoms and including at least one carbon-carbon double bond.Representative (C₂-C₃)alkenyls include -vinyl, -allyl, and1-prop-1-enyl.

In connection with the Z group and the

group, “—(C₂-C₃)alkenylene-” means a straight chain or branchednon-cyclic hydrocarbon moiety having 2 or 3 carbon atoms and includingat least one carbon-carbon double bond where two hydrogen atoms on thesame or a different carbon atom of the moiety are each figurativelyremoved and replaced by a bond to one of the two adjoining groups.Representative —(C₂-C₃)alkenylene-moieties include vin-1,1-diyl,vin-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl,prop-1-en-1,3-diyl, prop-2-en-1,1-diyl, and prop-2-en-1,3-diyl.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms andincluding at least one carbon-carbon triple bond. A branched alkynylmeans that one or more straight chain —(C₁-C₈)alkyl groups, such asmethyl, ethyl or propyl, replace one or both hydrogens in a —CH₂— groupof a straight chain alkynyl. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl, and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having 2, 3, 4, 5, or 6 carbon atoms and including at leastone carbon-carbon triple bond. Representative straight chain andbranched (C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, and the like.

“—(C₁-C₆)alkoxy” means a straight chain or branched non-cyclichydrocarbon having one or more ether groups and 1, 2, 3, 4, 5, or 6carbon atoms. Representative straight chain and branched (C₁-C₆)alkoxysinclude -methoxy, -ethoxy, -methoxymethyl, -2-methoxyethyl,-5-methoxypentyl, -3-ethoxybutyl, (methoxymethoxy)methyl-,1-(methoxy)-1-methoxyethyl-, trimethoxymethyl-,2-((methoxy)methoxy)-2-methylpropyl-, 3-(1,1,1-trimethoxypropane),(methoxy)trimethoxymethyl-, (2,2,2-trimethoxyethoxy)-, and the like.

“—(C₁-C₄)alkoxy” means a straight chain or branched non-cyclichydrocarbon having one or more ether groups and 1, 2, 3, or 4 carbonatoms. Representative straight chain and branched (C₁-C₄)alkoxys include-methoxy, -ethoxy, -methoxymethyl, -2-methoxyethyl,(methoxymethoxy)methyl-, 1-(methoxy)-1-methoxyethyl-, trimethoxymethyl-,and the like.

“—(C₃-C₁₄)cycloalkyl” means a saturated monocyclic hydrocarbon having 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. Representative(C₃-C₁₄)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl,-cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl,cycloundecyl, -cyclododecyl, and -cyclotetradecyl.

“—(C₃-C₁₂)cycloalkyl” means a saturated monocyclic hydrocarbon having 3,4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Representative(C₃-C₁₂)cycloalkyls are -cyclopropyl, -cyclobutyl, -cyclopentyl,-cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl,-cycloundecyl, and -cyclododecyl.

“—(C₆-C₁₂)cycloalkyl” means a saturated monocyclic hydrocarbon having 6,7, 8, 9, 10, 11, or 12 carbon atoms. Representative (C₆-C₁₂)cycloalkylsare -cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl,-cycloundecyl, and -cyclododecyl.

“—(C₄-C₈)cycloalkyl” or “4- to 8-member cycloalkyl ring” means asaturated monocyclic hydrocarbon having 4, 5, 6, 7, or 8 carbon atoms.Representative —(C₄-C₈)cycloalkyls are -cyclobutyl, -cyclopentyl,-cyclohexyl, -cycloheptyl, and -cyclooctyl.

“—(C₃-C₈)cycloalkyl” means a saturated monocyclic hydrocarbon having 3,4, 5, 6, 7, or 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and-cyclooctyl.

“—(C₃-C₇)cycloalkyl” means a saturated monocyclic hydrocarbon having 3,4, 5, 6, or 7 carbon atoms. Representative (C₃-C₇)cycloalkyls includecyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, and -cycloheptyl.

“—(C₆-C₁₄)bicycloalkyl” means a bicyclic hydrocarbon ring system having6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms and at least onesaturated cyclic alkyl ring. In one embodiment, the—(C₆-C₁₄)bicycloalkyl has one saturated cyclic alkyl ring. In anotherembodiment, the —(C₆-C₁₄)bicycloalkyl has two saturated cyclic alkylrings. Representative —(C₆-C₁₄)bicycloalkyls include -indanyl,-norbornyl, -1,2,3,4-tetrahydronaphthalenyl,-5,6,7,8-tetrahydronaphthalenyl, -perhydronaphthalenyl,-bicyclo[2.2.1]hexyl, bicyclo[2.2.1.]heptyl, -bicyclo[2.2.2]octyl,-bicyclo[3.3.1]heptyl, -bicyclo[3.2.1]octyl, -bicyclo[3.3.1]nonyl,-bicyclo[3.3.2]decyl, -bicyclo[3.3.3]undecyl, -bicyclo[4.2.2]decyl,-bicyclo[4.3.2]undecyl, -bicyclo[4.3.1]decyl, and the like.

“—(C₆-C₁₀)bicycloalkyl” means a bicyclic hydrocarbon ring system having6, 7, 8, 9, or 10 carbon atoms and at least one saturated cyclic alkylring. In one embodiment, the —(C₆-C₁₀)bicycloalkyl has one saturatedcyclic alkyl ring. In another embodiment, the —(C₆-C₁₀)bicycloalkyl hastwo saturated cyclic alkyl rings. Representative —(C₆-C₁₀)bicycloalkylsinclude -indanyl, -norbornyl, -1,2,3,4-tetrahydronaphthalenyl,-5,6,7,8-tetrahydronaphthalenyl, -perhydronaphthalenyl,-bicyclo[2.2.1]hexyl, bicyclo[2.2.1.]heptyl, -bicyclo[2.2.2]octyl,-bicyclo[3.3.1]heptyl, -bicyclo[3.2.1]octyl, -bicyclo[3.3.1]nonyl,-bicyclo[3.3.2]decyl, -bicyclo[4.2.2]decyl, -bicyclo[4.3.1]decyl, andthe like.

“—(C₈-C₂₀)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atomsand at least one saturated cyclic alkyl ring; thus, one of the rings cancomprise, e.g., benzo. In one embodiment, the —(C₈-C₂₀)tricycloalkyl hasone saturated cyclic alkyl ring. In another embodiment, the-(C₈-C₂₀)tricycloalkyl has two saturated cyclic alkyl rings. In anotherembodiment, the -(C₈-C₂₀)tricycloalkyl has three saturated cyclic alkylrings. Representative -(C₈-C₂₀)tricycloalkyls include -pyrenyl,-adamantyl, -noradamantyl, -1,2,3,4-tetrahydroanthracenyl,-1,2,3,4,4a,9,9a,10-octahydroanthracenyl, -perhydroanthracenyl-aceanthrenyl, -1,2,3,4-tetrahydropenanthrenyl,-5,6,7,8-tetrahydrophenanthrenyl,-1,2,3,4,4a,9,10,10a-octahydrophenanthrenyl, -perhydrophenanthrenyl,-tetradecahydro-1H-cyclohepta[a]naphthalenyl,-tetradecahydro-1H-cycloocta[e]indenyl,-tetradecahydro-1H-cyclohepta[e]azulenyl,-hexadecahydrocycloocta[b]naphthalenyl,-hexadecahydrocyclohepta[a]heptalenyl, -tricyclo-pentadecanyl,-tricyclo-octadecanyl, -tricyclo-nonadecanyl, -tricyclo-icosanyl,-2,3-benzobicyclo[2.2.2]octanyl, -6,7-benzobicyclo[3.2.1]octanyl,-9,10-benzobicyclo[3.3.2]decanyl, -2,3,4,4a,9,9a-hexahydro-1H-fluorenyl,-1,2,3,4,4a,8b-hexahydrobiphenylenyl, and the like.

“—(C₅-C₁₄)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and 5, 6, 7,8, 9, 10, 11, 12, 13, or 14 carbon atoms. Representative(C₅-C₁₄)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl,-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl,-cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,-cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclononatrienyl,-cyclodecenyl, -cyclodecadienyl, -cyclotetradecenyl, -cyclododecadienyl,and the like.

—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and 5, 6, 7, 8,9, or 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclononatrienyl, -cyclodecenyl, -cyclodecadienyl,and the like.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and 5, 6, 7, or8 carbon atoms. Representative (C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, and the like.

“—(C₇-C₁₄)bicycloalkenyl” means a bicyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and 7, 8, 9,10, 11, 12, 13, or 14 carbon atoms. Representative—(C₇-C₁₄)bicycloalkenyls include -indenyl, -pentalenyl, -naphthalenyl,-azulenyl, -heptalenyl, -1,2,7,8-tetrahydronaphthalenyl, -norbornenyl,and the like.

“—(C₇-C₁₀)bicycloalkenyl” means a bicyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and 7, 8, 9,or 10 carbon atoms. Representative —(C₇-C₁₀)bicycloalkenyls include-indenyl, -pentalenyl, -naphthalenyl, -azulenyl,-1,2,7,8-tetrahydronaphthalenyl, -norbornenyl, and the like.

“—(C₈-C₂₀)tricycloalkenyl” means a tricyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Representative—(C₈-C₂₀)tricycloalkenyls include -anthracenyl, -phenanthrenyl,-phenalenyl, -acenaphthalenyl, -as-indacenyl, -s-indacenyl,-2,3,6,7,8,9,10,11-octahydro-1H-cycloocta[e]indenyl,2,3,4,7,8,9,10,11-octahydro-1H-cyclohepta[a]naphthalenyl,-8,9,10,11-tetrahydro-7H-cyclohepta[a]naphthalenyl,-2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-cyclohepta[a]heptalenyl,-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-dicyclohepta[a,c]cyclooctenyl,-2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-dibenzo[a,d]cyclononenyl,and the like.

“-(5- to 8-membered)heterocycle”, “-(5- to 8-membered)heterocyclo”, or“-(5- to 8-membered)heterocyclic” means a 5- to 8-membered monocyclicheterocyclic ring, i.e., a monocyclic ring comprising at least oneheteroatom, which is either saturated, unsaturated non-aromatic oraromatic. A 5-membered heterocycle can contain 1, 2, 3, or 4heteroatoms, a 6-membered heterocycle can contain 1, 2, 3, or 4heteroatoms, and a 7- or 8-membered heterocycle can contain 1, 2, 3, 4,or 5 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The -(5- to 8-membered)heterocycle can beattached via a nitrogen or carbon atom. Representative -(5- to8-membered)heterocycles include pyridyl, furyl, thiophenyl, pyrrolyl,oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl, thiazolyl,isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl,tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl,tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, 1,4-oxazepanyl, azocanyl, 1,5-diazocanyl, and thelike.

“-(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3- to 7-membered monocyclic heterocyclic ring, i.e., amonocyclic ring comprising at least one heteroatom, which is eithersaturated, unsaturated non-aromatic or aromatic. A 3-memberedheterocycle contains 1 heteroatom, a 4-membered heterocycle can contain1 or 2 heteroatoms, a 5-membered heterocycle can contain 1, 2, 3, or 4heteroatoms, a 6-membered heterocycle can contain 1, 2, 3, or 4heteroatoms, and a 7-membered heterocycle can contain 1, 2, 3, 4, or 5heteroatoms. Each heteroatom is independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The -(3- to 7-membered)heterocycle can be attached via anitrogen or carbon atom. Representative -(3- to 7-membered)heterocyclesinclude pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl,thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, triazinyl, morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl,2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

“-(4-membered)heterocycle” or “-(4-membered)heterocyclo” means a4-membered monocyclic heterocyclic ring, i.e., a monocyclic ringcomprising at least one heteroatom, which is either saturated orunsaturated non-aromatic. A 4-membered heterocycle can contain 1 or 2heteroatoms. Each heteroatom is independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The -(4-membered)heterocycle can be attached via a nitrogen orcarbon atom. Representative -(4-membered)heterocycles include oxetane,thietane, azetine, and the like.

“-(7-membered)heterocycle” or “-(7-membered)heterocyclo” means a7-membered monocyclic heterocyclic ring, i.e., a monocyclic ringcomprising at least one heteroatom, which is either saturated orunsaturated non-aromatic. A 7-membered heterocycle can contain 1, 2, 3,4, or 5 heteroatoms. Each heteroatom is independently selected fromnitrogen, which can be quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. The -(7-membered)heterocycle can be attached viaa nitrogen or carbon atom. Representative -(7-membered)heterocyclesinclude oxepanyl, 1,4-dioxepanyl, azepanyl, 1,4-oxazepane, thiepanyl,1,3-oxathiepanyl, 1,3-thiazepanyl, 2,3-dihydro-1,3-thiazepinyl,2,3,4,5-tetrahydro-1,3-oxazepinyl, and the like.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo”means a 3- to 5-membered monocyclic heterocyclic ring, i.e., amonocyclic ring comprising at least one heteroatom, which is eithersaturated, unsaturated non-aromatic or aromatic. A 3-memberedheterocycle contains 1 heteroatom, a 4-membered heterocycle can contain1 or 2 heteroatoms, and a 5-membered heterocycle can contain 1, 2, 3, or4 heteroatoms. Each heteroatom is independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The -(3- to 5-membered)heterocycle can be attached via anitrogen or carbon atom. Representative -(3- to 5-membered)heterocyclesinclude furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl,thiazolidinyl, thiadiazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, oxiranyl,oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

“-(5- or 6-membered)heterocycle” or “-(5- or 6-membered)heterocyclo”means a 5- or 6-membered monocyclic heterocyclic ring, i.e., amonocyclic ring comprising at least one heteroatom, which is eithersaturated, unsaturated non-aromatic or aromatic. A 5-memberedheterocycle can contain 1, 2, 3, or 4 heteroatoms and a 6-memberedheterocycle can contain 1, 2, 3, or 4 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The -(5- or6-membered)heterocycle can be attached via a nitrogen or carbon atom.Representative -(5- or 6-membered)heterocycles include pyridyl, furyl,thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolidinyl, thiadiazolyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl,hydantoinyl, valerolactamyl, tetrahydrofuranyl, tetrahydropyranyl,dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrazolyl, and the like.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring, each ring of which is independently either saturated,unsaturated non-aromatic or aromatic, i.e., where at least one ringcomprises at least one heteroatom. A -(7- to10-membered)bicycloheterocycle contains 1, 2, 3, or 4 heteroatomsindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The -(7- to10-membered)bicycloheterocycle can be attached via a nitrogen or carbonatom. Representative -(7- to 10-membered)bicycloheterocycles include-quinolinyl, -isoquinolinyl, -2,3-dihydrobenzofuranyl,-1,3-dihydroisobenzofuranyl, -benzo[d][1,3]dioxolyl,-2,3-dihydrobenzo[b]thiophenyl, -1,3-dihydrobenzo[c]thiophenyl,-benzo[d][1,3]dithiolyl, -chromonyl, -chromanyl,-2,3-dihydrobenzo[b][1,4]dioxinyl, -thiochromonyl, -thiochromanyl,-2,3-dihydrobenzo[b][1,4]dithiinyl, -coumarinyl, -indolyl, -indolizinyl,-benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl, -purinyl,-4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,-naphthyridinyl, -indolinyl, -isoindolinyl,-1,2,3,4-tetrahydroquinolinyl, -1,2,3,4-tetrahydroisoquinolinyl, and thelike.

“—(C₃-C₁₂)cycloalkoxy” means a saturated monocyclic hydrocarbon having3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms where at least one ofthe carbon atoms is replaced by an oxygen atom. Representative(C₃-C₁₂)cycloalkoxy are -oxiranyl, -oxetanyl, -tetrahydrofuranyl,-tetrahydro-2H-pyranyl, -1,4-dioxanyl, -oxepanyl, -1,4-dioxepanyl,-oxocanyl, -1,5-dioxocanyl, -1,3,5-trioxocanyl, -oxonanyl,-1,5-dioxonanyl, -1,4,7-trioxonanyl, -oxacyclododecanyl,-1,7-dioxacyclododecanyl, and -1,5,9-trioxacyclododecanyl.

“—(C₃-C₇)cycloalkoxy” means a saturated monocyclic hydrocarbon having 3,4, 5, 6, or 7 carbon atoms where at least one of the carbon atoms isreplaced by an oxygen atom. Representative (C₃-C₇)cycloalkoxy are-oxiranyl, -oxetanyl, -tetrahydrofuranyl, -tetrahydro-2H-pyranyl,-1,4-dioxanyl, -oxepanyl, and -1,4-dioxepanyl.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as-anthryl or -phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, i.e., amonocyclic aromatic ring comprising at least one heteroatomindependently selected from nitrogen, oxygen, and sulfur or a bicyclicaromatic ring where at least one ring comprises at least one heteroatomindependently selected from nitrogen, oxygen, and sulfur. In oneembodiment, a monocyclic -(5- to 10-membered)heteroaryl comprises atleast two heteroatoms independently selected from nitrogen, oxygen, andsulfur. In another embodiment, a bicyclic -(5- to 10-membered)heteroarylcomprises at least two heteroatoms, present in the same or in differentrings, each heteroatom being independently selected from nitrogen,oxygen, and sulfur. In another embodiment, one of the -(5- to10-membered)heteroaryl's rings contain at least one carbon atom. Inanother embodiment, both of the bicyclic -(5- to10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, isoquinolinyl,pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl,thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolinyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidyl, pyrimidinyl, pyrazinyl,tliadiazolyl, triazinyl, thienyl, cinnolinyl, phthalazinyl, andquinazolinyl.

“-(5- or 6-membered)heteroaryl” means a monocyclic aromatic heterocyclering of 5 or 6 members, i.e., a monocyclic aromatic ring comprising atleast one heteroatom independently selected from nitrogen, oxygen, andsulfur. In one embodiment, the -(5- or 6-membered)heteroaryl ringcontains at least one carbon atom. Representative -(5- or6-membered)heteroaryls include pyridyl, furyl, pyrrolyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,3-triazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidyl, pyrazinyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,5-triazinyl, and thiophenyl.

“—CH₂(halo)” means a methyl group where one of the hydrogens of themethyl group has been replaced with a halogen. Representative —CH₂(halo)groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of themethyl group have each been independently replaced with a halogen.Representative —CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, —CHBrC1,—CHClI, and —CHI₂.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been independently replaced with a halogen.Representative —C(halo)₃ groups include —CF₃, —CCl₃, —CBr₃, —Cl₃,—CF₂Br, —CF₂Cl, —CCl₂F, and —CFClBr.

“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.

“Oxo”, “═O”, and the like as used herein mean an oxygen atom doublybonded to carbon or another element.

“Thiooxo”, “thioxo”, “═S”, and the like as used herein mean a sulfuratom doubly bonded to carbon or another element.

“(C₂-C₆)bridge” as used herein means a hydrocarbon chain containing 2 to6 carbon atoms joining two atoms of the piperidine ring of Formula (I)to form a fused bicyclic ring system. For example, compounds of thedisclosure can comprise a (C₂-C₆)bridge joining positions 2 and 6 of thepiperidine ring (A-B can together form a (C₂-C₆)bridge). Exemplarycompounds of the disclosure include those with an unsubstituted(C₂)bridge, —CH₂—CH₂—, joining positions 2 and 6 of the piperidine ring(A-B can together form a (C₂)bridge); an unsubstituted (C₃)bridge,—CH₂—CH₂—CH₂—, joining positions 2 and 6 of the piperidine ring (A-B cantogether form a (C₃)bridge); an unsubstituted (C₄)bridge,—CH₂—CH₂—CH₂—CH₂—, joining positions 2 and 6 of the piperidine ring (A-Bcan together form a (C₄)bridge); an unsubstituted (C₅)bridge,—CH₂—CH₂—CH₂—CH₂—CH₂—, joining positions 2 and 6 of the piperidine ring(A-B can together form a (C₅)bridge); or an unsubstituted (C₆)bridge,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, joining positions 2 and 6 of the piperidinering (A-B can together form a (C₆)bridge). Examples of compounds whereA-B can together form a (C₂-C₆)bridge include compounds comprising thefollowing ring systems: 8-aza-bicyclo[3.2.1]octane;9-aza-bicyclo[3.3.1]nonane; 10-aza-bicyclo[4.3.1]decane;11-aza-bicyclo[5.3.1]undecane; and 12-aza-bicyclo[6.3.1]dodecane.Examples of a (C₂-C₆)bridge which contains —HC═CH— within the(C₂-C₆)bridge include —HC═CH—, —CH₂—HC═CH—, —HC═CH—CH₂—,—CH₂—HC═CH—CH₂—, and the like. Examples of a (C₂-C₆)bridge whichcontains —O— within the (C₂-C₆)bridge include —CH₂—O—CH₂-(containing 2carbon atoms), —CH₂—O—CH₂—CH₂— and —CH₂—CH₂—O—CH₂— (each containing 3carbon atoms), —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂— and—CH₂—CH₂—CH₂—O—CH₂— (each containing 4 carbon atoms), and the like.

It is to be understood that when t is 0, the compounds of formula (IA)and the like are represented as:

where the Q_(x) ring is, e.g., a -(4-, 5-, 6-, or 7-membered)heterocycleas defined for formula (IA) above; when t is 0 and the dashed linewithin the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring is present, the compounds of formula (IA) and the like arerepresented as:

where the Q_(x) ring is, e.g., a -(4-, 5-, 6-, or 7-membered)heterocycleas defined for formula (IA) above; and when t is 0, the dashed linewithin the 5-membered, nitrogen-containing ring that is fused to theQ_(a) ring is absent, and the other dashed line is present, thecompounds of formula (IA) and the like are represented as:

where the Q_(x) ring is, e.g., a -(4-, 5-, 6-, or 7-membered)heterocycleas defined for formula (IA) above.

It is to be understood that when t is 1, the compounds of formula (IA)and the like are represented as:

where the Q_(x) ring is, e.g., a (6-membered)heterocycle as defined forformula (IA) above; when t is 1 and the dashed line within the5-membered, nitrogen-containing ring that is fused to the Q_(a) ring ispresent, the compounds of formula (IA) and the like are represented as:

where the Q_(x) ring is, e.g., a (6-membered)heterocycle as defined forformula (IA) above; and when t is 1, the dashed line within the5-membered, nitrogen-containing ring that is fused to the Q_(a) ring isabsent, and the other dashed line is present, the compounds of formula(IA) and the like are represented as:

where the Q_(x) ring is, e.g., a (6-membered)heterocycle as defined forformula (IA) above.

It is to be understood that when t is 2, the compounds of formula (IA)and the like are represented as:

where the Q_(x) ring is, e.g., a (6-membered)heterocycle as defined forformula (IA) above; when t is 2 and the dashed line within the5-membered, nitrogen-containing ring that is fused to the Q_(a) ring ispresent, the compounds of formula (IA) and the like are represented as:

where the Q_(x) ring is, e.g., a (6-membered)heterocycle as defined forformula (IA) above; and when t is 2, the dashed line within the5-membered, nitrogen-containing ring that is fused to the Q_(a) ring isabsent, and the other dashed line is present, the compounds of formula(IA) and the like are represented as:

where the Q_(x) ring is, e.g., a (6-membered)heterocycle as defined forformula (IA) above.

In compounds of the disclosure comprising a bridge joining positions 2and 6 of the piperidine ring (e.g., A-B can together form a(C₂-C₆)bridge), for, e.g., a compound of Formula (I), the exemplary endobridge:

is equivalent to

In compounds of the disclosure comprising a bridge joining positions 2and 6 of the piperidine ring (e.g., A-B can together form a(C₂-C₆)bridge), for, e.g., a compound of Formula (I), the exemplary exobridge:

is equivalent to

In compounds of the disclosure where the —Z—R¹ group comprises abicyclic group, that bicyclic group can have two orientations. Forexample, for a —Z—R¹ group that is a —(C₆-C₁₄)bicycloalkyl, e.g.,bicyclo[3.3.1]nonanyl, attached directly to the piperidine ringnitrogen, the following orientations are possible:

As used herein in connection with “—[(C₁-C₁₀)alkyl optionallysubstituted by R¹³]_(h)—”, when h is 1 means that the Z—R¹ bonded to thepiperidine ring bearing A and B substituents is understood to appear asfollows:

where, when i is 0, the —(C₁-C₁₀)alkyl- is unsubstituted by a R¹³ groupand, when i is 1, the —(C₁-C₁₀)alkyl- is substituted by a R¹ group atthe carbon atom furthest removed from the piperidine ring bearing A andB substituents and substituted by a R¹³ group at any carbon atom of the—(C₁-C₁₀)alkyl-including at the carbon atom furthest removed from thepiperidine ring bearing A and B substituents. In one embodiment, R¹³ isselected from:

-   -   (a) -halo, —OH, —CH₂OH, —CH₂CH₂OH, —N(R⁶)₂, and —C(═O)OV¹; and    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —O(C₁-C₆)alkyl,        —(C₅-C₁₄)cycloalkenyl, and -(5- or 6-membered)heterocycle, each        of which is unsubstituted or substituted with 1, 2, 3, or 4        independently selected R⁸ groups; and    -   (c)

-   -   wherein R¹⁴ is —H and n is an integer selected from 2, 3, 4, 5,        6, and 7;    -   (d) -phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1 or 2 independently selected        R⁷ groups.        In another embodiment, R¹³ is selected from:    -   (a) -halo, —OH, —CH₂OH, —CH₂CH₂OH, —N(R⁶)₂, and —C(═O)OV¹; and    -   (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —O(C₁-C₄)alkyl, and -(5- or        6-membered)heterocycle, each of which is unsubstituted or        substituted with 1 or 2 independently selected R⁵ groups; and    -   (c)

-   -   Wherein R¹⁴ is —H and n is an integer selected from 2, 3, 4, 5,        6, and 7;    -   (d) -phenyl and -(5- or 6-membered)heteroaryl, each of which is        unsubstituted or substituted with 1 or 2 independently selected        R⁷ groups.

“—[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—” as used herein inconnection with Z—R¹ means that the Z—R¹ bonded to the piperidine ringbearing A and B substituents is understood to appear as follows:

where, when i is 0, the —(C₂-C₁₀)alkenyl- is unsubstituted by a R¹³group and, when i is 1, the —(C₂-C₁₀)alkenyl- is substituted by a R¹group at the carbon atom furthest removed from the piperidine ringbearing A and B substituents and substituted by a R¹³ group at anycarbon atom of the —(C₂-C₁₀)alkenyl-including at the carbon atomfurthest removed from the piperidine ring bearing A and B substituents.

As used herein in connection with formula (i) of R¹, when the dashedline is present as a bond to provide a double bond at that position,then formula (i) is understood to appear as follows

As used herein in connection with formula (i) of R¹, when the dashedline is absent, then formula (i) is understood to appear as follows

As used herein in connection with formula (iv) of R¹³, when the dashedline is present as a bond to provide a double bond at that position,then formula (iv) is understood to appear as follows

As used herein in connection with formula (iv) of R¹³, when the dashedline is absent, then formula (iv) is understood to appear as follows

The terms “benzo,” “benzo group” and the like, when used in connectionwith the Q_(a) ring, means

where R², and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I).

The terms “pyridino,” “pyridino group” and the like, when used inconnection with the Q_(a) ring, means

where R², and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted pyridino Q_(a) ring is

In another embodiment, the optionally-substituted pyridino Q_(a) ring is

In another embodiment, the optionally-substituted pyridino Q_(a) ring is

In another embodiment, the optionally-substituted pyridino Q_(a) ring is

The terms “pyrimidino”, “pyrimidino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted pyrimidino Q_(a) ring is

In another embodiment, the optionally-substituted pyrimidino Q_(a) ringis

The terms “pyrazino”, “pyrazino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I).

The terms “pyridazino”, “pyridazino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted pyridazino Q_(a) ring is

In another embodiment, the optionally-substituted pyridazino Q_(a) ringis

In another embodiment, the optionally-substituted pyridazino Q_(a) ringis

The terms “pyrrolino”, “pyrrolino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted pyrrolino Q_(a) ring is

In another embodiment, the optionally-substituted pyrrolino Q_(a) ringis

In another embodiment, the optionally-substituted pyrrolino Q_(a) ringis

The terms “imidazolino”, “imidazolino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted imidazolino Q_(a) ring is

In another embodiment, the optionally-substituted imidazolino Q_(a) ringis

The terms “pyrazolino”, “pyrazolino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted pyrazolino Q_(a) ring is

In another embodiment, the optionally-substituted pyrazolino Q_(a) ringis

In another embodiment, the optionally-substituted pyrazolino Q_(a) ringis

In another embodiment, the optionally-substituted pyrazolino Q_(a) ringis

The terms “triazolino”, “triazolino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted triazolino Q_(a) ring is

In another embodiment, the optionally-substituted triazolino Q_(a) ringis

The terms “furano”, “furano group” and the like, when used in connectionwith the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted furano Q_(a) ring is

In another embodiment, the optionally-substituted furano Q_(a) ring is

In another embodiment, the optionally-substituted furano Q_(a) ring is

The terms “oxazolino”, “oxazolino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted oxazolino Q_(a) ring is

In another embodiment, the optionally-substituted oxazolino Q_(a) ringis

The terms “isoxazolino”, “isoxazolino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted isoxazolino Q_(a) ring is

In another embodiment, the optionally-substituted isoxazolino Q_(a) ringis

In another embodiment, the optionally-substituted isoxazolino Q_(a) ringis

In another embodiment, the optionally-substituted isoxazolino Q_(a) ringis

The terms “oxadiazolino”, “oxadiazolino group” and the like, when usedin connection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted oxadiazolino Q_(a) ring is

In another embodiment, the optionally-substituted oxadiazolino Q_(a)ring is

In another embodiment, the optionally-substituted oxadiazolino Q_(a)ring is

The terms “thiopheno”, “thiopheno group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted thiopheno Q_(a) ring is

In another embodiment, the optionally-substituted thiopheno Q_(a) ringis

In another embodiment, the optionally-substituted thiopheno Q_(a) ringis

The terms “thiazolino”, “thiazolino group” and the like, when used inconnection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted thiazolino Q_(a) ring is

In another embodiment, the optionally-substituted thiazolino Q_(a) ringis

The terms “isothiazolino”, “isothiazolino group” and the like, when usedin connection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted isothiazolino Q_(a) ring is

In another embodiment, the optionally-substituted isothiazolino Q_(a)ring is

In another embodiment, the optionally-substituted isothiazolino Q_(a)ring is

In another embodiment, the optionally-substituted isothiazolino Q_(a)ring is

The terms “thiadiazolino”, “thiadiazolino group” and the like, when usedin connection with the optionally-substituted Q_(a) ring, means

where R² and a are defined above for the Substituted Benzimidazole-TypePiperidine Compounds of Formula (I). In one embodiment, theoptionally-substituted thiadiazolino Q_(a) ring is

In another embodiment, the optionally-substituted thiadiazolino Q_(a)ring is

In another embodiment, the optionally-substituted thiadiazolino Q_(a)ring is

In one embodiment, the term “optionally substituted bicyclo[3.3.1]nonyl”and the like when used in connection with the optionally-substituted R¹group is understood to refer to one of the structures below:

where the substituents are as defined above for the SubstitutedBenzimidazole-Type Piperidine Compounds of Formula (I); and where in oneor more embodiments, the optionally substituted R¹ group comprises oneor more of the above-recited optionally substituted bicycle[3.3.1]nonylstructures.

In one embodiment, the term “optionally substituted—(C₆-C₁₄)bicycloalkyl” means

where the dashed line denotes the presence or absence of a bond (i.e.,when a dashed line is present there is a double bond at that positionand when a dashed line is absent there is a single bond at thatposition). when the dashed line is present as a bond to provide a doublebond at that position, then the group above is understood to appear asfollows

and when the dashed line is absent, then the optionally substituted—(C₆-C₁₄)bicycloalkyl group above is understood to appear as follows

In one embodiment, the term “2-(1H-imidazole)” means

In one embodiment, the term “2-(1-methyl-1H-imidazole)” means

In one embodiment, the term “S(═O)₂-4-(3,5-dimethylisoxazole)” means

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different. Inone embodiment, a first group is substituted with up to three secondgroups. In another embodiment, a first group is substituted with one ortwo second groups. In another embodiment, a first group is substitutedwith two second groups. In another embodiment, a first group issubstituted with two second groups and each second group is identical.In another embodiment, a first group is substituted with only one secondgroup.

The term “animal” includes, but is not limited to, a human or anon-human animal, such as a companion animal or livestock, e.g., a cow,monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit or guinea pig.

The term “pharmaceutically acceptable derivative”, as used herein,includes any pharmaceutically acceptable salt, solvate, radiolabeledform, stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of aSubstituted Benzimidazole-Type Piperidine Compound of the disclosure.

In one embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, solvate, radiolabeled form,stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of aSubstituted Benzimidazole-Type Piperidine Compound of the disclosure.The term “pharmaceutically acceptable salt”, as used herein, is anypharmaceutically acceptable salt that can be prepared from a SubstitutedBenzimidazole-Type Piperidine Compound including a salt formed from anacid and a basic functional group, such as a nitrogen group, of aSubstituted Benzimidazole-Type Piperidine Compound. Illustrative saltsinclude, but are not limited, to sulfate, citrate, acetate,trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a Substituted Benzimidazole-Type Piperidine Compoundhaving an acidic functional group, such as a carboxylic acid functionalgroup, and a pharmaceutically acceptable inorganic or organic base.

Suitable bases include, but are not limited to, hydroxides of alkalimetals such as sodium, potassium, cesium, and lithium; hydroxides ofalkaline earth metal such as calcium and magnesium; hydroxides of othermetals, such as aluminum and zinc; ammonia and organic amines, such asunsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;dicyclohexylamine; tributyl amine; pyridine; picoline;N-methyl-N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-(C₁-C₃)alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine,N,N-di-[(C₁-C₃)alkyl]-N-(hydroxy-(C₁-C₃)alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. In one embodiment, the pharmaceutically acceptable salt is ahydrochloride-salt, a sulfate-salt, a sodium-salt, a potassium-salt, abenzene sulfonic acid-salt, a para-toluenesulfonic acid-salt, or afumaric acid-salt. In another embodiment, the pharmaceuticallyacceptable salt is a hydrochloride-salt or a sulfate-salt. In anotherembodiment, the pharmaceutically acceptable salt is ahydrochloride-salt. In another embodiment, the pharmaceuticallyacceptable salt is a sulfate-salt. In another embodiment, thepharmaceutically acceptable salt is a sodium-salt. In anotherembodiment, the pharmaceutically acceptable salt is a potassium-salt. Inanother embodiment, the pharmaceutically acceptable salt is apara-toluenesulfonic acid-salt. In another embodiment, thepharmaceutically acceptable salt is a fumaric acid-salt. In anotherembodiment, the pharmaceutically acceptable fumaric acid-salt containsabout one equivalent of a Substituted Benzimidazole-Type PiperidineCompound and about 0.5 equivalents of fumaric acid, e.g., from about 0.3to about 0.7 equivalents of fumaric acid in one embodiment, from about0.4 to about 0.6 equivalents of fumaric acid in another embodiment, fromabout 0.44 to about 0.56 equivalents of fumaric acid in anotherembodiment, or from about 0.47 to about 0.53 equivalents of fumaric acidin another embodiment. In another embodiment, the pharmaceuticallyacceptable fumaric acid-salt contains one equivalent of a SubstitutedBenzimidazole-Type Piperidine Compound and 0.5 equivalents of fumaricacid. One skilled in the art will recognize that, e.g., acid additionsalts, of a Substituted Benzimidazole-Type Piperidine Compound can beprepared by reaction of the compounds with the appropriate acid by avariety of known methods.

The compounds of the disclosure provided herein also encompass allanhydrates of the Substituted Benzimidazole-Type Piperidine Compounds.The term “anhydrate” as used herein, is any crystalline form of aSubstituted Benzimidazole-Type Piperidine Compound in which watermolecules are a non-integral part of the crystal. An anhydrate of aSubstituted Benzimidazole-Type Piperidine Compound can be prepared, forexample, by crystallization from a solvent substantially free of water.In one embodiment, the Substituted Benzimidazole-Type PiperidineCompound is present as an anhydrate, i.e., as a free base where thecrystal lattice is substantially free of water molecules and any watermolecules present are present as “surface water” (e.g., loosely bound tothe crystal's surface) as would be discernable and distinguishable tothose in the art by, e.g., thermogravimetric analysis (TGA) and/ordifferential scanning calorimetry (DSC), from water molecules that arean integral part of the crystal (e.g., a hydrate). An anhydrate of aSubstituted Benzimidazole-Type Piperidine Compound has less than about0.2 mole water in one embodiment, less than about 0.15 mole water inanother embodiment, less than about 0.12 mole water in anotherembodiment, less than about 0.1 mole water in another embodiment, lessthan about 0.085 mole water in another embodiment, less than about 0.075mole water in another embodiment, less than about 0.06 mole water inanother embodiment, less than about 0.057 mole water in anotherembodiment, less than about 0.05 mole water in another embodiment, lessthan about 0.03 mole water in another embodiment, less than about 0.025mole water in another embodiment, less than about 0.02 mole water inanother embodiment, less than about 0.01 mole water in anotherembodiment, less than about 0.005 mole water in another embodiment, andless than about 0.001 mole water in another embodiment, each saidembodiment taking into account the presence of surface water and eachsaid embodiment being per 1 mole of a Substituted Benzimidazole-TypePiperidine Compound.

The compounds of the disclosure provided herein also encompass allsolvates of the Substituted Benzimidazole-Type Piperidine Compounds.“Solvates” are known in the art and are considered to be a combination,physical association and/or solvation of a SubstitutedBenzimidazole-Type Piperidine Compound with a solvent molecule. Thisphysical association can involve varying degrees of ionic and covalentbonding, including hydrogen bonding. When the solvate is of thestoichiometric type, there is a fixed ratio of the solvent molecule toSubstituted Benzimidazole-Type Piperidine Compound, e.g., a disolvate,monosolvate or hemisolvate when the solvent molecule: SubstitutedBenzimidazole-Type Piperidine Compound molecule molar ratio is 2:1, 1:1or 1:2, respectively. In other embodiments, the solvate is of thenonstoichiometric type. For example, the Substituted Benzimidazole-TypePiperidine Compound crystal can contain solvent molecules in thestructural voids, e.g., channels, of the crystal lattice. In certaininstances, the solvate can be isolated, for example when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate”, as used herein, encompasses bothsolution-phase and isolatable solvates. A Substituted Benzimidazole-TypePiperidine Compound of the disclosure can be present as a solvated formwith a pharmaceutically acceptable solvent, such as water, methanol,ethanol, and the like, and it is intended that the disclosure includeboth solvated and unsolvated Substituted Benzimidazole-Type PiperidineCompound forms. As “hydrate” relates to a particular subgroup ofsolvates, i.e., where the solvent molecule is water, hydrates areincluded within the solvates of the disclosure. In one embodiment, theSubstituted Benzimidazole-Type Piperidine Compound is present as amonohydrate, i.e., as a free base where the water:SubstitutedBenzimidazole-Type Piperidine Compound molar ratio is about 1:1, e.g.,from 0.91:1 to 1.09:1 in one embodiment, from 0.94:1 to 1.06:1 inanother embodiment, from 0.97:1 to 1.03:1 in another embodiment, andfrom 0.985:1 to 1.015:1 in another embodiment, each said embodimenttaking no account of surface water that might be present, if any.

Preparation of solvates is known in the art. For example, Caira et al.,“Preparation and Crystal Characterization of a Polymorph, a Monohydrate,and an Ethyl Acetate Solvate of the Antifungal Fluconazole,” J.Pharmaceut. Sci., 93(3):601-611 (2004), describes the preparation ofsolvates of fluconazole with ethyl acetate and with water. Similarpreparations of solvates, hemisolvate, hydrates, and the like aredescribed by Van Tonder et al., “Preparation and PhysicochemicalCharacterization of 5 Niclosamide Solvates and 1 Hemisolvate,” AAPSPharm. Sci. Tech., 5(1):Article 12 (2004), and Bingham et al., “Over onehundred solvates of sulfathiazole,” Chem. Comm., pp. 603-604 (2001). Inone embodiment, a non-limiting, process involves dissolving theSubstituted Benzimidazole-Type Piperidine Compound in a desired amountof the desired solvent (organic, water or mixtures thereof) attemperatures above about 20° C. to about 25° C., cooling the solution ata rate sufficient to form crystals, and isolating the crystals by knownmethods, e.g., filtration. Analytical techniques, for example, infraredspectroscopy, can be used to show the presence of the solvent in acrystal of the solvate.

In addition, one or more hydrogen, carbon or other atoms of aSubstituted Benzimidazole-Type Piperidine Compound can be replaced by aradioactive isotope of the hydrogen, carbon or other atoms. Such a“radiolabeled”, “radiolabeled form”, and the like of a SubstitutedBenzimidazole-Type Piperidine Compound, each of which is encompassed bythe disclosure, is useful as a research and/or diagnostic tool inmetabolism pharmacokinetic studies and in binding assays. “Radioactive”,as used herein with respect to an atom, means an atom that comprises aradioactive atom and therefore the specific radioactivity thereof isabove the background level of radioactivity. Examples of radioactiveisotopes that can be incorporated into a Substituted Benzimidazole-TypePiperidine Compound of the disclosure include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine,bromine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ¹⁹F, ³⁶Cl, ³⁷Cl, ⁷⁶Br, ⁷⁷Br, ⁸¹Br, ¹²³I, ¹²⁴I, ¹²⁵I, and¹³¹I, respectively. In one embodiment, a radiolabeled SubstitutedBenzimidazole-Type Piperidine Compound contains 1, 2, 3, 4, or moreradioactive isotopes, each of which is independently selected fromhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, bromine, and iodine. In another embodiment, a radiolabeledSubstituted Benzimidazole-Type Piperidine Compound contains 1 or 2radioactive isotopes, each of which is independently selected fromhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, bromine, and iodine. In another embodiment, a radiolabeledSubstituted Benzimidazole-Type Piperidine Compound contains 1radioactive isotope which is selected from hydrogen, carbon, nitrogen,oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. Inanother embodiment, a radiolabeled Substituted Benzimidazole-TypePiperidine Compound contains 1, 2, 3, 4, or more radioactive isotopes,each of which is independently selected from ²H, ³H, , ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁹F, ¹⁹F, ³⁶Cl, ³⁷Cl, ⁷⁶Br, ⁷⁷Br, ⁸¹Br,¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. In another embodiment, a radiolabeledSubstituted Benzimidazole-Type Piperidine Compound contains 1 or 2radioactive isotopes, each of which is independently selected from ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹⁹F, ³⁶Cl, ³⁷Cl,⁷⁶Br, ⁷⁷Br, ⁸¹Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. In another embodiment, aradiolabeled Substituted Benzimidazole-Type Piperidine Compound contains1 radioactive isotope which is selected from ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹⁹F, ³⁶Cl, ³⁷Cl, ⁷⁶Br, ⁷⁷Br, ⁸¹Br, ¹²³I,¹²⁴I, ¹²⁵I, and ¹³¹I. In another embodiment, a radiolabeled SubstitutedBenzimidazole-Type Piperidine Compound contains 1, 2, 3, 4, or moreradioactive isotopes, each of which is independently selected from ²H,³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, and ¹²⁵I. In another embodiment, aradiolabeled Substituted Benzimidazole-Type Piperidine Compound contains1 or 2 radioactive isotopes, each of which is independently selectedfrom ³H, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, and ¹²⁵I. In another embodiment, aradiolabeled Substituted Benzimidazole-Type Piperidine Compound contains1 radioactive isotope which is selected from ³H, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, and¹²⁵I.

Radiolabeled compounds of the disclosure can be prepared by methodsknown in the art. For example, tritiated Substituted Benzimidazole-TypePiperidine Compounds can be prepared by introducing tritium into theparticular Substituted Benzimidazole-Type Piperidine Compound, forexample, by catalytic dehalogenation with tritium. This method caninclude reacting a suitably halogen-substituted precursor of aSubstituted Benzimidazole-Type Piperidine Compound with tritium gas inthe presence of a suitable catalyst, for example, Pd/C, in the presenceor absence of a base. Other suitable methods for preparing tritiatedcompounds can be found in Filer, “The Preparation and Characterizationof Tritiated Neurochemicals,” Isotopes in the Physical and BiomedicalSciences, Vol. 1, Labeled Compounds (Part A), E. Buncel et al, eds.,Chapter 6, pp. 155-192 (1987). ¹⁴C-labeled compounds can be prepared byemploying starting materials having a ¹⁴C carbon. Compounds containingpiperazine isotopcially enriched with ¹³C and/or ¹⁵N can be prepared asdescribed in, e.g., FIG. 5A and the associated description, of U.S. Pat.No. 7,355,045 B2. Radiolabeled compounds containing ¹⁸F at the6-position of an aniline ring can be prepared as described in column 27of U.S. Pat. No. 6,562,319 B2.

An Substituted Benzimidazole-Type Piperidine Compound can contain one ormore asymmetric centers and can thus give rise to enantiomers,diastereomers, and other stereoisomeric forms. Unless specificallyotherwise indicated, the disclosure encompasses compounds with all suchpossible forms as well as their racemic and resolved forms or anymixture thereof. When a Substituted Benzimidazole-Type PiperidineCompound contains an olefinic double bond or other center of geometricasymmetry, and unless specifically otherwise indicated, it is intendedto include all “geometric isomers”, e.g., both E and Z geometricisomers. Unless specifically otherwise indicated, all “tautomers”, e.g.,lactam-lactim, urea-isourea, ketone-enol, amide-imidic acid,enamine-imine, amine-imine, and enamine-enimine tautomers, are intendedto be encompassed by the disclosure as well.

As used herein, the terms “stereoisomer”, “stereoisomeric form”, and thelike are general terms for all isomers of individual molecules thatdiffer only in the orientation of their atoms in space. It includesenantiomers and isomers of compounds with more than one chiral centerthat are not mirror images of one another (“diastereomers”).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically active wherethe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomerswhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule. Opticalisomers of a Substituted Benzimidazole-Type Piperidine

Compound can be obtained by known techniques such as chiralchromatography or formation of diastereomeric salts from an opticallyactive acid or base.

Optical purity can be stated in terms of enantiomeric excess (% ee)and/or diastereomeric excess (% de), each which is determined by theappropriate formula below:

${\% \mspace{14mu} {ee}} = {\lbrack \frac{{{major}\mspace{14mu} {enantiomer}\; ({mol})} - {{minor}\mspace{14mu} {enantiomer}\; ({mol})}}{{{major}\mspace{14mu} {enantiomer}\; ({mol})} + {{minor}\mspace{14mu} {enantiomer}\; ({mol})}} \rbrack \times 100\%}$${\% \mspace{14mu} {de}} = {\lbrack \frac{{{major}\mspace{14mu} {diastereomer}\; ({mol})} - {{minor}\mspace{14mu} {diastereomers}\; ({mol})}}{{{major}\mspace{14mu} {diastereomer}\; ({mol})} + {{minor}\mspace{14mu} {diastereomers}\; ({mol})}} \rbrack \times 100{\%.}}$

The term “MeOH” means methanol, i.e., methyl alcohol. The term “EtOH”means ethanol, i.e., ethyl alcohol. The term “Et₂O” means diethyl ether,i.e., ethoxyethane. The term “THF” means tetrahydrofuran. The term “DMF”means N,N-dimethylformamide. The term “DCM” means methylene chloride,i.e., dichloromethane or CH₂Cl₂. The term “DCE” means1,2-dichloroethane. The term “EtOAc” means ethyl acetate. The term“MeCN” means acetonitrile. The term “DMSO” means dimethylsulfoxide,i.e., methylsulfinylmethane. The term “NMP” means N-methylpyrrolidinone,i.e., 1-methylpyrrolidin-2-one. The term “MTBE” means tert-butyl methylether, i.e., 2-methoxy-2-methylpropane. The term “AcOH” means aceticacid. The term “TFA” means 2,2,2-trifluoroacetic acid. The term “TEA”means triethylamine. The term “DIEA” means diisopropylethylamine, i.e.,N-ethyl-N-isopropylpropan-2-amine. The term “Bn” means benzyl, i.e.:

The term “NaOH” means sodium hydroxide. The term “HCl” meanshydrochloric acid. The term “EDCI” means1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, i.e.,N¹-((ethylimino)methylene)-N³, N³-dimethylpropane-1,3-diamine. The term“CDI” means di(1H-imidazol-1-yl)methanone. The term “BOC” meanstert-butyloxycarbonyl, i.e.:

The term “IBD” means inflammatory-bowel disease. The term “IBS” meansirritable-bowel syndrome. The term “ALS” means amyotrophic lateralsclerosis.

The term “effective amount”, when used in connection with a SubstitutedBenzimidazole-Type Piperidine Compound, means an amount effective for:(a) treating or preventing a Condition or symptom thereof; (b)detectably inhibiting ORL-1 receptor function in a cell; or (c)detectably activating ORL-1 receptor function in a cell.

The term “effective amount”, when used in connection with a secondtherapeutic agent means an amount for providing the therapeutic effectof the second therapeutic agent.

The terms “modulate”, “modulating”, and the like as used herein withrespect to the ORL-1 receptor mean the mediation of a pharmacodynamicresponse (e.g., analgesia) in an animal from (i) inhibiting oractivating the receptor, or (ii) directly or indirectly affecting thenormal regulation of the receptor activity. Compounds that modulate thereceptor activity include agonists, partial agonists, antagonists, mixedagonists/antagonists, mixed partial agonists/antagonists and compoundswhich directly or indirectly affect regulation of the receptor activity.

As used herein, a compound that binds to a receptor and mimics theregulatory effect(s) of an endogenous ligand is defined as an “agonist”.As used herein, a compound that binds to a receptor and is only partlyeffective as an agonist is defined as a “partial agonist”. As usedherein, a compound that binds to a receptor but produces no regulatoryeffect, but rather blocks binding of another agent to the receptor isdefined as an “antagonist”. (See Ross et al., “Pharmacodynamics:Mechanisms of Drug Action and the Relationship Between DrugConcentration and Effect,” in Goodman and Gilman's The PharmacologicalBasis of Therapeutics pp. 31-43 (Goodman et al., eds., 10^(th) Ed.,McGraw-Hill, New York 2001)).

The terms “treatment of”, “treating”, and the like include theamelioration or cessation of a Condition or a symptom thereof. In oneembodiment, treating includes inhibiting, for example, decreasing theoverall frequency of episodes of a Condition or a symptom thereof.

The terms “prevention of”, “preventing”, and the like include theavoidance of the onset of a Condition or a symptom thereof.

A “disorder” includes, but is not limited to, the Conditions definedabove.

In the event of doubt as to the agreement of a depicted chemicalstructure and a chemical name, the depicted chemical structure governs.

It is appreciated that various features of the disclosure which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment unless otherwisespecifically herein excluded. Conversely, various features of thedisclosure which are, for brevity, described in the context of a singleembodiment, can also be provided separately and/or in any suitablesubcombination unless otherwise specifically herein excluded.

4.5 METHODS FOR MAKING SUBSTITUTED BENZIMIDAZOLE-TYPE PIPERIDINECOMPOUNDS OF FORMULA (I)

Substituted Benzimidazole-Type Piperidine Compounds can be made usingconventional organic synthesis, in view of the present disclosure, andincluding the following illustrative methods shown in the schemes belowwhere R¹, R², R³, Q_(a), W, U, A, B, Z, a, and the dashed lines aredefined above, L is a halogen leaving group such as Br or I, L′ is F orCl, R is —(C₁-C₄)alkyl or —CF₃, and R¹ is —(C₁-C₄)alkyl. For simplicity,in the following schemes the exemplary Q_(a) group is benzo which issometimes unsubstituted with R²; however, the schemes are alsoapplicable to substituted benzo and any of the (5- or 6-membered)heteroaryl Q_(a) groups, whether unsubstituted or optionallysubstituted.

Section 4.5.1 describes methods for making benzene-1,2-diaminecompounds. Section 4.5.2 describes methods for making SubstitutedBenzimidazole-Type Piperidine Compounds of Formula (I) frombenzene-1,2-diamine compounds. Section 4.5.3 describes methods formaking various stereochemical forms of Substituted Benzimidazole-TypePiperidine Compounds of Formula (I).

4.5.1 Methods for Making Benzene-1,2-diamine Compounds

Preparation of Substituted Benzimidazole-Type Piperidine Compounds ofFormula (I) can be carried out by reacting through a benzene-1,2-diamineintermediate compound (e.g., Compound A4). Five alternative methods forpreparing benzene-1,2-diamine compounds are shown in Schemes A and C—Fbelow.

4.5.1.1 Synthesis of Compound A4: Method 1 (Scheme A)

In Scheme A and the other schemes, “Lit 1” refers to the proceduresdescribed in the publications Tortolani et al., “A Convenient Synthesisto N-Aryl-Substituted 4-Piperidones,” Org. Lett. 1:1261-1262 (1999)and/or International PCT Publication No. WO 2005/075459 A1 ofEuro-Celtique S. A. and “Lit 2” refers to the procedures described inU.S. Pat. No. 6,635,653 by Goehring et al.

Compounds A1 and A2 are commercially available or can be prepared bymethods known to the art.

A piperidinium salt of structure A1 can be reacted with a primary aminein a suitable solvent, such as EtOH, under reflux conditions in thepresence of a base, such as potassium carbonate, as described inreference “Lit 1” to provide the 1-(substituted)piperidine-4-oneCompound A3. As described in reference “Lit 2,” Compound A3 can also beprepared by alkylation of a piperidine-4-one of structure A2 with analkyl bromide or alkyl iodide in a suitable solvent, such as DMF, MeCNor DMSO, in the presence of an inorganic base, such as potassiumcarbonate, or an organic base, such as DIEA. As described in reference“Lit 2,” Compound A3 can also be prepared by reductive amination ofCompound A2 with an aldehyde or ketone using either sodiumtriacetoxyborohydride or sodium cyanoborohydride in a suitable solvent,such as DCM or MeOH, respectively. Compound A3 can then be reductivelyaminated with a substituted or unsubstituted 1,2-phenylenediamine usingsodium triacetoxyborohydride or sodium cyanoborohydride in a suitablesolvent, such as DCM or MeOH, respectively, to provide Compound A4, asdescribed in reference “Lit 2.”

4.5.1.2 Synthesis of Compound B6: Method 2 (Scheme B)

In Scheme B and the other schemes, “Lit 3” refers to the referenceRylander, “Hydrogenation of Nitro Compounds,” in Hydrogenation Methodspp. 104-116 (Academic Press, London, 1985), which provides a review ofthe methods available for the reduction of nitro groups, and “Lit 4”refers to the Zinin reduction procedures described in the referencePorter, “The Zinin Reduction of Nitroarenes,” Org. Reactions, 20:455-481(1973).

Compound B1 is commercially available or can be prepared by methodsknown to the art. Compound B1 can be reacted with an acid chlorideRC(═O)Cl, such as 2,2,2-trifluoroacetyl chloride, or anhydride(RC(═O))₂O, such as 2,2,2-trifluoroacetic anhydride, and a base, such asTEA, in a suitable solvent, such as DCM or THF, to provide Compound B2.Compound B2 can be converted to Compound B3 in a two step procedure byhydrolysis of the ester to the carboxylic acid using an appropriatebase, such as aqueous NaOH, followed by treatment with diphenylphosphorazidate (“(PhO)₂P(═O)N₃”) and phenylmethanol (“BnOH”) underCurtius rearrangement conditions. The benzyloxycarbonyl group ofCompound B3 can then be removed under hydrogenolysis conditions using anoble metal catalyst, e.g., palladium on carbon, under a hydrogenatmosphere, to provide Compound B4. Compound B4 can be reacted with asubstituted or unsubstituted 2-halo-1-nitrobenzene (where the halo isfluoride or chloride) in the presence of a base such as potassiumcarbonate in a suitable solvent such as MeCN under reflux conditions toprovide Compound B5. In the next step, Compound B5 can be converted toCompound B6 using a catalyst, such as Raney nickel, in a suitablesolvent, such as EtOH, under a hydrogen atmosphere as described inreference “Lit 3.” Compound B5 can also be converted to Compound B6 bychemical means, such as with Zn, Sn(II) chloride or Fe, or usingsulfides or polysulfides by the Zinin Reduction as described inreference “Lit 4.”

4.5.1.3 Synthesis of Compound C4: Method 3 (Scheme C)

Compound C1 is commercially available or can be prepared from CompoundB1 by methods known to the art. Compound C2 can be prepared fromCompound C1 in a similar manner to the preparation of Compound B4 fromCompound B1 in Scheme B. Compound C2 can be reacted with a substitutedor unsubstituted 2-halo-1-nitrobenzene (where the halo is fluoride orchloride) in the presence of a base such as potassium carbonate in asuitable solvent such as MeCN under reflux conditions to provideCompound C3. In the next step, Compound C3 can be converted to CompoundC4 by treatment with a hydrogenation catalyst, such as Raney nickel, ina suitable solvent, such as EtOH, under a hydrogen atmosphere, or bychemical means using a reducing agent, such as Zn, Sn(II) chloride orFe, or using sulfide or polysulfides by the Zinin Reduction as describedin Scheme B.

4.5.1.4 Synthesis of Compound D2: Method 4 (Scheme D)

As shown in Scheme D, Compound A3 can be converted to Compound D1 underreductive amination conditions using a BOC protected, substituted orunsubstituted 1,2-phenylenediamine and a reducing agent, such as sodiumtriacetoxyborohydride or sodium cyanoborohydride, in a suitable solvent,such as DCM or MeOH, respectively as described in reference “Lit 2.” TheBOC protecting group can be removed using acidic conditions, such asusing HCl or TFA, to provide Compound D2. Where substituent groups A andB together form a bridge, e.g., a two carbon bridge, the “exo” and“endo” isomers which result can be conveniently separated using flashcolumn chromatography.

4.5.1.5 Synthesis of Compound E3: Method 5 (Scheme E)

In Scheme E, Compound E3 can be prepared as described in U.S. Pat. App.Pub. No. US 2010/0022519 A1 for example, at paragraph [1364] andthereafter. Briefly, the primary amine E1, where —Z—R¹ can becyclodecyl, adamantyl or noradamantyl, for example, can be treated witha piperidone salt in a polar solvent, such as EtOH or MeOH containingwater, and an inorganic base, such as potassium carbonate, under refluxfor from about 4 hrs to about 6 hrs to provide Compound E2. Compound E2can then be treated with a substituted or unsubstituted1,2-phenylenediamine and AcOH in a solvent, such as THF or1,2-dimethoxyethane, to provide an imine, which can be reduced withsodium triacetoxyborohydride to provide Compound E3.

4.5.2 Methods for Making Substituted Benzimidazole-Type PiperidineCompounds of Formula (I) from Benzene-1,2-diamine Compounds

Methods for converting benzene-1,2-diamine compounds to provideSubstituted Benzimidazole-Type Piperidine Compounds of Formula (I) areshown in Schemes F-P below.

4.5.2.1 Synthesis of Substituted Benzimidazole-Type Piperidine CompoundsWhere Q_(x) is Present and U¹ is C or CH (Schemes F-H)

In Scheme F, Compound A4 can be reacted with Compound F1 in the presenceof one or more coupling reagents, e.g., 1-hydroxybenzotriazole (HOBT)and/or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), at atemperature of about 25° C. to provide Compound F2. The reaction can becarried out in the presence of a suitable base, such as DIEA.

In Scheme F′, Compound A4 can be reacted with Compound F1′ in excesssodium bisulfite at an elevated temperature (e.g., greater than about100° C.) to provide Compound F2′. In certain embodiments, the reactioncan be carried out using a microwave apparatus as an energy source.

In Scheme G, Compound F2 can be cyclized in the presence of an acid toprovide Substituted Benzimidazole-Type Piperidine Compound G1. Incertain embodiments, the cyclization reaction is conducted in thepresence of AcOH at elevated temperature, e.g., from about 80° C. toabout 120° C.

In Scheme H, acylation or alkylation of a Q_(x) ring nitrogen atom ofSubstituted Benzimidazole-Type Piperidine Compound G1 in the presence ofa base provides Substituted Benzimidazole-Type Piperidine Compound H1.

4.5.2.1.1 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where Q_(x) is Present, U¹ is C or CH, and R³ and/or R⁴ isCH₂C(═O)OH (Scheme J)

In Scheme J, Substituted Benzimidazole-Type Piperidine Compound G1 isreacted with L-CH₂C(═O)OCH₃ in the presence of a base to provideSubstituted Benzimidazole-Type Piperidine Compounds J1 and J2.Substituted Benzimidazole-Type Piperidine Compound J1 and/or SubstitutedBenzimidazole-Type Piperidine Compound J2 can then be hydrolyzed by asuitable base, e.g., NaOH, in EtOH to provide SubstitutedBenzimidazole-Type Piperidine Compound J3 and/or SubstitutedBenzimidazole-Type Piperidine Compound J4, respectively.

4.5.2.2 Synthesis of Substituted Benzimidazole-Type Piperidine CompoundsWhere is a Single Bond, Q_(x) is Present, and U¹ is N (Schemes K and L)

In Scheme K, Compound A4 can be reacted with CDI in a suitable organicsolvent, e.g., THF, to provide cyclized compound K1. Compound K1 canthen be brominated at an elevated temperature through the addition ofphosphorus oxybromide (POBr₃) in a suitable organic solvent, e.g., DCE,to provide Compound K2.

In Scheme L, Compound K2 is reacted with Compound L1 under aminationconditions, for example, using an amination agent, such asN,N-dicyclohexylcarbodiimide, HOBT, or EDCI, and a base, such as TEA orDIEA, in a suitable solvent, such as DCM or THF, to provide SubstitutedBenzimidazole-Type Piperidine Compound L2. In certain embodiments, thereaction can be conducted in a sealed pressurized tube at elevatedtemperature, e.g., about 100° C.

4.5.2.3 Synthesis of Substituted Benzimidazole-Type Piperidine CompoundsWhere is —CH₂—, Q_(x) is Present, and U¹ is N (Scheme M)

In Scheme M, Compound A4 can be cyclized at elevated temperature, e.g.,from about 70° C. to about 120° C., through the addition of Compound M1in the presence of a strong acid to provide SubstitutedBenzimidazole-Type Piperidine Compound M2. SubstitutedBenzimidazole-Type Piperidine Compound M2 can then be reacted withCompound L1 in the presence of base to provide SubstitutedBenzimidazole-Type Piperidine Compound M3.

4.5.2.4 Synthesis of Substituted Benzimidazole-Type Piperidine CompoundsWhere is —NH— and Q_(x) is Absent (Scheme N)

In Scheme N, Compound A4 can be reacted with isocyanate N1 in thepresence of a suitable organic solvent, e.g., DCM, to provide compoundN2. Compound N2 can then be cyclized through the addition of phosphorusoxychloride (POCl₃) at elevated temperature, e.g., about 100° C., toprovide Substituted Benzimidazole-Type Piperidine Compound N3.

4.5.2.5 Synthesis of Substituted Benzimidazole-Type Piperidine CompoundsWhere is —CH₂— and Q_(x) is Absent (Scheme O)

In Scheme O, Compound A4 can be acylated through a reaction withCompound O1 in a suitable organic solvent to provide Compound O2.Compound O2 can be cyclized through the addition of an acid, e.g., AcOH,at an elevated temperature, e.g., about 100° C., to provide SubstitutedBenzimidazole-Type Piperidine Compound O3.

4.5.2.6 Synthesis of Substituted Benzimidazole-Type Piperidine CompoundsWhere is —CH═N— and Q_(x) is Absent

Substituted Benzimidazole-Type Piperidine Compound P1 in Scheme P can beprepared, e.g., by the method in Section 4.5.2.5 above. SubstitutedBenzimidazole-Type Piperidine Compound P1 can be converted toSubstituted Benzimidazole-Type Piperidine Compound P2 through theaddition of magnesium dioxide in a suitable organic solvent, e.g., DCM.Substituted Benzimidazole-Type Piperidine Compound P2 can then bereacted with Compound P3 in an alcohol solvent, e.g., MeOH, under refluxconditions to provide Substituted Benzimidazole-Type Piperidine CompoundP4.

4.5.3 Methods for Making Specific Stereoisomeric Forms of SubstitutedBenzimidazole-Type Piperidine Compounds of Formula (I)

Specific stereoisomeric forms of Substituted Benzimidazole-TypePiperidine Compounds of Formula (I) can be prepared using methodsdescribed above. As described below, the desired stereochemical form canbe introduced into the optionally-bridged piperidine portion of themolecule prior to the addition of the quinoxaline portion of themolecule.

4.5.3.1 Synthesis of Stereoisomeric Forms of SubstitutedBenzimidazole-Type Piperidine Compound Precursors (Scheme Q)

In Scheme Q, Compound Q3 can be prepared according to the methodsdescribed in U.S. Pat. App. Pub. No. US 2010/0216726 A1, for example, atparagraph [1745] and thereafter. Briefly, Compound Q1 can be convertedto oxime Compound Q2 using aqueous hydroxylamine in an acidic solvent,such as AcOH. Compound Q2 can be reduced to an endo amine Compound Q3 byhydrogenation using a noble metal catalyst, such as platinum oxide, in asolvent, such as AcOH.

4.5.3.2 Alternative Synthesis of Stereoisomeric Forms of SubstitutedBenzimidazole-Type Piperidine Compound Precursors (Scheme R)

In Scheme R and the other schemes, “Lit 5” refers to Berdini et al., “AModified Palladium Catalyzed Reductive Amination Procedure,”Tetrahedron, 58:5669-5674 (2002) and “Lit 6” refers to Lewin et al.,“Molecular Features Associated with Polyamine Modulation of NMDAReceptors,” J. Med. Chem. 41:988-995 (1998).

Compound Q1, where substituent groups A and B together form a bridge,e.g., a two carbon bridge, is commercially available or can be preparedby methods known to the art.

When substituent groups A and B together form a bridge, e.g., a twocarbon bridge, Compound Q1 can be converted to Compound Q3, the “endo”isomer, under reductive amination conditions using, e.g., ammoniumformate and a noble metal catalyst, e.g., palladium on carbon, in asolvent, such as EtOH or MeOH, as described in reference “Lit 5.”Similarly, where substituent groups A and B together form a bridge,e.g., a two carbon bridge, Compound Q1 can be reacted with aqueoushydroxylamine in a solvent, such as hexanes, to form an intermediatehydroxylamine, which can be converted to its oxime by dehydration in asolvent with a high boiling point, such as toluene, under Dean-starkconditions. The oxime intermediate can be converted to Compound R1, the“exo” isomer, by reduction using, e.g., sodium in propanol as describedin reference “Lit 6.”

4.5.3.3 Synthesis of Stereoisomeric Forms of SubstitutedBenzimidazole-Type Piperidine Compounds of Formula (I) from Compound O3(Scheme S)

In Scheme S, Compound S2 can be prepared according to the methodsdescribed in U.S. Pat. App. Pub. No. US 2010/0216726 A1, for example, atparagraph [1745] and thereafter. Briefly, amine Compound Q3 or its salt,such as the acetate, can be reacted with a substituted or unsubstituted2-fluoronitrobenzene in a polar solvent, such as MeCN or DMF, and abase, such as TEA or potassium carbonate, to provide Compound S1.Compound S1 can be reduced to Compound S2 by hydrogenation using a noblemetal catalyst, such as palladium on charcoal or Raney nickel, in asolvent, such as EtOAc or DCM. Thereafter, a SubstitutedBenzimidazole-Type Piperidine Compound of Formula (I) can be preparedusing methods described in Sections 4.5.1 through 4.5.2.

In these embodiments, the final product of the reaction, i.e., theSubstituted Benzimidazole-Type Piperidine Compound of Formula (I), has apercent diastereomeric excess (% de) of at least about 90%. In anotherembodiment, the final product of the reaction has a % de of at leastabout 95%. In another embodiment, the final product of the reaction hasa % de of at least about 97%. In another embodiment, the final productof the reaction has a % de of at least about 98%. In another embodiment,the final product of the reaction has a % de of at least about 99%. Inanother embodiment, the final product of the reaction has a % de ofgreater than 99% (e.g., 99.1% to 99.9%).

4.5.4 Methods for Making 3-Chloroquinoxalin-2(1H)-one Intermediates andSubstituted Benzimidazole-Type Piperidine Compounds Comprising a3-(Bicyclo[3.3.1]nonanyl) R¹ Group (Scheme T)

In Scheme T, 2-adamantanone T1 can be dissolved in TFA and treated witha peracid, such sodium percarbonate, at from about 20° C. to about 30°C. to provide a lactone Compound T2. Compound T2 can be hydrolyzed to ahydroxyl acid using NaOH in a solvent, such as MeOH, under reflux. Thestereochemistry of the acid epimerizes from endo to exo. The hydroxylacid can be dehydrated to Compound T3 using an acid, such asmethanesulfonic acid, in a solvent, such as toluene, by azeotropicdrying. Compound T3 can be hydrogenated using a catalyst, such aspalladium on charcoal, in a mixed solvent system, such as MeOH andEtOAc, to provide a mixture of acid Compound T4 and its methyl ester(Compound T4′, not shown). The mixture can be hydrolyzed to the acidCompound T4 using NaOH in aqueous MeOH. Compound T4 can be converted toCompound T5 using di-phenyl phosphoryl azide and TEA in a solvent, suchas toluene, in a Curtius type reaction to provide an isocyanate that canbe hydrolyzed to the amine of Compound T5 using NaOH in aqueous THF oranother aprotic water miscible solvent. The isolated amine of CompoundT5 can be converted to its hydrochloride salt by treatment with HCl.Compound T5 can be converted to a 2-chloroquinoxaline Compound T6according to the methods described in Section 4.5.1. Compound T6 can beconverted to Substituted Benzimidazole-Type Piperidine Compounds ofFormula (I′) according to the methods described in Section 4.5.2.

4.5.5 Methods for Making 3-Chloroquinoxalin-2(1H)-one Intermediates andSubstituted Benzimidazole-Type Piperidine Compounds Comprising a3-(7-Methylbicyclo[3.3.1]nonanyl) R¹ Group (Scheme U)

In Scheme U, 1,3-dihydroxyadamantane U1 can be treated withp-toluenesulfonyl chloride in pyridine at a temperature of about 70° C.for from about 2 hr to about 6 hr to provide Compound U2. Compound U2can be hydrogenated to Compound U3 using platinum oxide in a non-polarsolvent, such cyclohexane. Compound U3 can be converted to the oximeCompound U4 using hydroxylamine in AcOH at a temperature from about 25°C. to about 40° C. Compound U4 can be reacted with sodium metal andiso-propanol in a solvent, such as toluene, at a temperature of about100° C. to provide the amine of Compound U5. The isolated amine ofCompound U5 can be converted to its hydrochloride salt by treatment withHCl in a solvent, such as Et₂O. Compound U5 can be converted to CompoundU6 according to the methods described in Section 4.5.1.1. Compound U6can be converted to Substituted Benzimidazole-Type Piperidine Compoundsof Formula (I″) according to the method described in Section 4.5.2.

4.6 Therapeutic Uses of the Substituted Benzimidazole-Type PiperidineCompounds

In accordance with the disclosure, the Substituted Benzimidazole-TypePiperidine Compounds are administered to an animal in need of treatmentor prevention of a Condition.

In one embodiment, an effective amount of a SubstitutedBenzimidazole-Type Piperidine Compound can be used to treat or preventany condition treatable or preventable by inhibiting the activity of theORL-1 receptor. Examples of Conditions that are treatable or preventableby inhibiting the activity of the ORL-1 receptor include, but are notlimited to: pain (CNS effect), memory disorders, obesity, constipation,depression, dementia, and Parkinsonism.

In another embodiment, an effective amount of a SubstitutedBenzimidazole-Type Piperidine Compound can be used to treat or preventany condition treatable or preventable by activating the ORL-1 receptor.Examples of Conditions that are treatable or preventable by activatingthe ORL-1 receptor include, but are not limited to, pain (PNS effect),anxiety, cough, diarrhea, blood pressure disorder (via vasodilation andvia diuresis), epilepsy, anorexia/cachexia, urinary incontinence, drugabuse, a sleep disorder, a metabolic disorder, a renal disorders, and acardiovascular disorder.

The Substituted Benzimidazole-Type Piperidine Compounds can be used totreat or prevent acute or chronic pain. Examples of pain that can betreated or prevented using a Substituted Benzimidazole-Type PiperidineCompound include, but are not limited to, cancer pain, neuropathic pain,labor pain, myocardial infarction pain, pancreatic pain, colic pain,post-operative pain, headache pain, muscle pain, arthritic pain, andpain associated with a periodontal disease, including gingivitis andperiodontitis.

The Substituted Benzimidazole-Type Piperidine Compounds can also be usedto treat or prevent pain associated with inflammation or with aninflammatory disease in an animal. Such pain can arise where there is aninflammation of the body tissue which can be a local inflammatoryresponse or a systemic inflammation. For example, a SubstitutedBenzimidazole-Type Piperidine Compound can be used to treat or preventpain associated with inflammatory diseases including, but not limitedto, organ transplant rejection; reoxygenation injury resulting fromorgan transplantation (see Grupp et al., “Protection againstHypoxia-reoxygenation in the Absence of Poly (ADP-ribose) Synthetase inIsolated Working Hearts,” J. Mol. Cell Cardiol. 31:297-303 (1999))including, but not limited to, transplantation of the heart, lung,liver, or kidney; chronic inflammatory diseases of the joints, includingarthritis, rheumatoid arthritis, osteoarthritis and bone diseasesassociated with increased bone resorption; inflammatory bowel diseases,such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn'sdisease; inflammatory lung diseases, such as asthma, adult respiratorydistress syndrome, and chronic obstructive airway disease; inflammatorydiseases of the eye, including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory disease of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory disease of the skin, including sclerodermatitis,psoriasis and eczema; inflammatory diseases of the central nervoussystem, including chronic demyelinating diseases of the nervous system,multiple sclerosis, AIDS-related neurodegeneration and Alzheimer'sdisease, infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis; autoimmune diseases, including Type I and TypeII diabetes mellitus; diabetic complications, including, but not limitedto, diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroalbuminuria and progressive diabetic nephropathy), gangrene of thefeet, atherosclerotic coronary arterial disease, peripheral arterialdisease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, jointproblems, and a skin or mucous membrane complication (such as aninfection, a shin spot, a candidal infection or necrobiosis lipoidicadiabeticorum), immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory disease of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andartherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. An SubstitutedBenzimidazole-Type Piperidine Compound can also be used to treat orprevent pain associated with inflammatory disease that can, for example,be a systemic inflammation of the body, exemplified by gram-positive orgram negative shock, hemorrhagic or anaphylactic shock, or shock inducedby cancer chemotherapy in response to pro-inflammatory cytokines, e.g.,shock associated with pro-inflammatory cytokines. Such shock can beinduced, e.g., by a chemotherapeutic agent that is administered as atreatment for cancer.

The Substituted Benzimidazole-Type Piperidine Compounds can also be usedto treat or prevent pain associated with nerve injury (i.e., neuropathicpain). Chronic neuropathic pain is a heterogenous disease state with anunclear etiology. In chronic neuropathic pain, the pain can be mediatedby multiple mechanisms. This type of pain generally arises from injuryto the peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. The chronic pain is differentfrom acute pain in that chronic neuropathic pain patients suffer theabnormal pain sensations that can be described as spontaneous pain,continuous superficial burning and/or deep aching pain. The pain can beevoked by heat-, cold-, and mechano-hyperalgesia, or by heat-, cold-, ormechano-allodynia.

Chronic neuropathic pain can be caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to, pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain can also be caused by nerve damage from chronicalcoholism, human immunodeficiency virus infection, hypothyroidism,uremia, or vitamin deficiencies. Stroke (spinal or brain) and spinalcord injury can also induce neuropathic pain. Cancer-related neuropathicpain results from tumor growth compression of adjacent nerves, brain, orspinal cord. In addition, cancer treatments, including chemotherapy andradiation therapy, can cause nerve injury. Neuropathic pain includes butis not limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The Substituted Benzimidazole-Type Piperidine Compounds can be used totreat or prevent a migraine including, but not limited to, migrainewithout aura (“common migraine”), migraine with aura (“classicmigraine”), migraine without headache, basilar migraine, familialhemiplegic migraine, migrainous infarction, and migraine with prolongedaura.

The Substituted Benzimidazole-Type Piperidine Compounds can be used totreat or prevent a sleep disorder including, but not limited to,insomnia, hypersomnia, sleep deprivation, sleep apnea, dysomnia, delayedsleep phase syndrome (DSPS), advanced sleep phase syndrome (ASPS),non-24-hour sleep-wake syndrome (e.g., circadian rhythm sleep disorder),situational circadian rhythm sleep disorders (e.g., jet lag, shift worksleep disorders), hypopnea, irregular sleep wake rhythm, nightmares,night terror, parasomnia, restless leg syndrome (RLS), nocturnalmycolonus/periodic limb movement disorder (PLMD), rapid eye movement(REM) sleep disorder, somnambulism/sleep walking, somniloquy/sleeptalking, and somniphobia. For example, U.S. Pat. No. 8,003,669 disclosesa class of ORL-1 agonists said to be therapeutic agents for circadianrhythm sleep disorder and Miyakawa et al. disclose that administrationof the ORL-1 receptor agonist known as W-212393 induces phase advance oflocomotor activity circadian rhythm in mice (“ORL1 receptor-mediateddown-regulation of mPER2 in the suprachiasmatic nucleus acceleratesre-entrainment of the circadian clock following a shift in theenvironmental light/dark cycle,” Neuropharmacol. 52:1055-1064 (2007)).

Metabolic disorders can be caused by an abnormal metabolic process andcan be acquired, e.g., failure of a metabolically important organ suchas the liver or disease of an endocrine organ, or congenital, e.g., aninherited enzyme abnormality. A congenital metabolic disorder can becaused by a defect in a single gene; some of the more well-known inbornmetabolic errors include sickle cell anemia, hypothyroidism, Tay-Sachsdisease, phenylketonuria, and cystic fibrosis. The SubstitutedBenzimidazole-Type Piperidine Compounds can be used to treat or preventa metabolic disorder including, but not limited to, anorexia nervosa,bulimia, and obesity. For example, U.S. Pat. No. 7,241,770 discloses aclass of hydronopol derivative ORL-1 agonists said to be therapeuticagents for metabolic disorders.

A renal disorder may be acute or chronic. An acute renal disorder can becaused by impaired blood flow to the kidneys due to, e.g., blood loss,heart attack, or liver failure; kidney damage due to, e.g., blood clots,hemolytic uremic syndrome, or vasculitis; or urine blockage due to,e.g., bladder cancer, an enlarged prostate, or kidney stones. A chronicrenal disorder can be caused by, e.g., diabetes mellitus, hypertension,or polycystic kidney disease. The Substituted Benzimidazole-TypePiperidine Compounds can be used to treat or prevent a renal disorderincluding, but not limited to, those renal disorders characterized bythe syndrome of inappropriate antidiuretic hormone secretion (SIADH) orby imbalances of water retention and/or water excretion or saltexcretion. For example, U.S. Pat. No. 6,869,960 discloses a class ofspiropiperidine ORL-1 ligands said to be therapeutic agents for renaldisorders.

Cardiovascular disorders represent the leading cause of death in theUnited States, responsible for about 27% of yearly deaths.Cardiovascular disorders can be caused by tobacco use, alcohol abuse,obesity, diabetes mellitus, high cholesterol, high blood pressure, andother factors. The Substituted Benzimidazole-Type Piperidine Compoundscan be used to treat or prevent a cardiovascular disorder including, butnot limited to, myocardial infarction, arrhythmias, bradycardia,hypertension, hypotension, thrombosis, anemia, arteriosclerosis, andangina pectoris. For example, U.S. Pat. No. 7,241,770 discloses a classof hydronopol derivative ORL-1 agonists said to be therapeutic agentsfor cardiovascular disorders.

According to the disclosure, some of the Substituted Benzimidazole-TypePiperidine Compounds are agonists at the ORL-1 receptor, some of theSubstituted Benzimidazole-Type Piperidine Compounds are partial agonistsat the ORL-1 receptor, and some of the Substituted Benzimidazole-TypePiperidine Compounds are antagonists at the ORL-1 receptor. In anotherembodiment, a Substituted Benzimidazole-Type Piperidine Compound is anagonist at the ORL-1 receptor and an agonist at a μ, κ and/or δ opioidreceptor, particularly at a μ opioid receptor. In another embodiment, aSubstituted Benzimidazole-Type Piperidine Compound is a partial agonistat the ORL-1 receptor and an agonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor. In another embodiment, aSubstituted Benzimidazole-Type Piperidine Compound is an antagonist atthe ORL-1 receptor and an agonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor. In another embodiment, aSubstituted Benzimidazole-Type Piperidine Compound is an agonist at theORL-1 receptor and an antagonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor. In another embodiment, aSubstituted Benzimidazole-Type Piperidine Compound is a partial agonistat the ORL-1 receptor and an antagonist at a μ, κ and/or δ opioidreceptor, particularly at a μ opioid receptor. In another embodiment, aSubstituted Benzimidazole-Type Piperidine Compound is an antagonist atthe ORL-1 receptor and an antagonist at a μ, κ and/or δ opioid receptor,particularly at a μ opioid receptor.

The disclosure also provides methods for inhibiting ORL-1 receptorfunction in a cell, comprising contacting a cell capable of expressingthe ORL-1 receptor with an amount of a Substituted Benzimidazole-TypePiperidine Compound effective to inhibit ORL-1 receptor function in thecell. This method can be adapted for use in vitro as part of an assay toselect compounds that can be useful for treating or preventing aCondition in an animal. Alternatively, this method can be adapted foruse in vivo, (i.e., in an animal such as a human) by contacting a cellin the animal with an effective amount of a SubstitutedBenzimidazole-Type Piperidine Compound. In one embodiment, the method isuseful for treating or preventing pain in an animal in need of suchtreatment or prevention. In another embodiment, the method is useful fortreating or preventing a memory disorder, obesity, constipation,depression, dementia, or Parkinsonism in an animal in need of suchtreatment or prevention.

The disclosure also relates to methods for activating ORL-1 receptorfunction in a cell, comprising contacting a cell capable of expressingthe ORL-1 receptor with an amount of a Substituted Benzimidazole-TypePiperidine Compound effective to activate ORL-1 receptor function in thecell. This method can be adapted for use in vitro as part of an assay toselect compounds useful for treating or preventing, pain, anxiety,cough, diarrhea, high blood pressure, epilepsy, anorexia/cachexia,urinary incontinence, drug abuse, a sleep disorder, a metabolicdisorder, a renal disorders, or a cardiovascular disorder.Alternatively, the method can be adapted for use in vivo (i.e., in ananimal such as a human), by contacting a cell in the animal with aneffective amount of a Substituted Benzimidazole-Type PiperidineCompound. In one embodiment, the method is useful for treating orpreventing pain in an animal in need of such treatment or prevention. Inanother embodiment, the method is useful for treating or preventinganxiety, cough, diarrhea, high blood pressure, epilepsy,anorexia/chachexia, urinary incontinence, drug abuse, a sleep disorder,a metabolic disorder, a renal disorders, or a cardiovascular disorder inan animal in need of such treatment or prevention.

Examples of tissue comprising cells capable of expressing the ORL-1receptor include but are not limited to brain, spinal cord, vasdeferens, and gastrointestinal tract tissue. Methods for assaying cellsthat express the ORL-1 receptor are known in the art; for example, seeShimohigashi et al., “Sensitivity of Opioid Receptor-like Receptor ORL1for Chemical Modification on Nociceptin, a Naturally OccurringNociceptive Peptide,” J. Biol. Chem. 271(39):23642-23645 (1996); Naritaet al., “Identification of the G-protein Coupled ORL1 Receptor in theMouse Spinal Cord by [³⁵S]-GTPγS Binding and Immunohistochemistry,”Brit. J. Pharmacol. 128:1300-1306 (1999); Milligan, “Principles:Extending the Utility of [³⁵S]GTPγS Binding Assays,” TIPS 24(2):87-90(2003); and Lazareno, “Measurement of Agonist-stimulated [³⁵S]GTPγSBinding to Cell Membranes,” Methods in Molecular Biology 106:231-245(1999).

4.7 Therapeutic/Prophylactic Administration and Compositions of theDisclosure

Due to their activity, the Substituted Benzimidazole-Type PiperidineCompounds are advantageously useful in human and veterinary medicine. Asdescribed above, the Substituted Benzimidazole-Type Piperidine Compoundsare useful for treating or preventing a Condition in an animal in needthereof. The Substituted Benzimidazole-Type Piperidine Compounds of thedisclosure can be administered to any animal requiring modulation of theopioid and/or ORL-1 receptors.

When administered to an animal, a Substituted Benzimidazole-TypePiperidine Compound can be administered as a component of a compositionthat comprises a pharmaceutically acceptable carrier or excipient. Thecompositions, which comprise a Substituted Benzimidazole-Type PiperidineCompound, can be administered orally. An Substituted Benzimidazole-TypePiperidine Compound can also be administered by any other convenientroute, for example, by infusion or bolus injection, by absorptionthrough epithelial or mucocutaneous linings (e.g., oral, rectal, andintestinal mucosa, etc.) and can be administered together with a secondtherapeutically active agent. Administration can be systemic or local.Various delivery systems are known, e.g., encapsulation in liposomes,microparticles, microcapsules, multiparticulates, capsules, etc., andcan be used to administer a Substituted Benzimidazole-Type PiperidineCompound.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intracerebral, intravaginal,transdermal (e.g., via a patch), rectal, by inhalation, transmucosal, ortopical, particularly to the ears, nose, eyes, or skin. The method ofadministration is left to the discretion of the practitioner. In someinstances, administration will result in the release of a SubstitutedBenzimidazole-Type Piperidine Compound into the bloodstream. In otherinstances, administration will result in only local release of aSubstituted Benzimidazole-Type Piperidine Compound.

In specific embodiments, it can be desirable to administer a SubstitutedBenzimidazole-Type Piperidine Compound locally. This can be achieved,for example and not by way of limitation, by local infusion duringsurgery, topical application, e.g., in conjunction with a wound dressingafter surgery, by injection, by means of a catheter, by means of asuppository or enema, or by means of an implant, said implant being of aporous, non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce a SubstitutedBenzimidazole-Type Piperidine Compound into the central nervous systemor gastrointestinal tract by any suitable route, includingintraventricular, intrathecal, and epidural injection, and enema.Intraventricular injection can be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, a Substituted Benzimidazole-Type PiperidineCompound can be formulated as a suppository, with traditional bindersand excipients such as triglycerides.

When a Substituted Benzimidazole-Type Piperidine Compound of thedisclosure is incorporated for parenteral administration by injection(e.g., continuous infusion or bolus injection), the formulation forparenteral administration can be in the form of a suspension, solution,emulsion in an oily or aqueous vehicle, and such formulations canfurther comprise pharmaceutically necessary additives such as one ormore stabilizing agents, suspending agents, dispersing agents, and thelike. An Substituted Benzimidazole-Type Piperidine Compound of thedisclosure can also be in the form of a powder for reconstitution as aninjectable formulation.

In another embodiment, a Substituted Benzimidazole-Type PiperidineCompound can be delivered in a vesicle, in particular a liposome (seeLanger, “New Methods of Drug Delivery,” Science 249:1527-1533 (1990);and Treat et al., “Liposome Encapsulated Doxorubicin Preliminary Resultsof Phase I and Phase II Trials,” pp. 317-327 and 353-365 in Liposomes inthe Therapy of Infectious Disease and Cancer (1989)).

In yet another embodiment, a Substituted Benzimidazole-Type PiperidineCompound can be delivered in a controlled-release system orsustained-release system (see, e.g., Goodson, “Dental Applications,” inMedical Applications of Controlled Release, Vol. 2, Applications andEvaluation, Langer and Wise, eds., CRC Press, Chapter 6, pp. 115-138(1984), hereafter “Goodson”). Other controlled- or sustained-releasesystems discussed in the review by Langer, Science 249:1527-1533 (1990)can be used. In one embodiment, a pump can be used (Langer, Science249:1527-1533 (1990); Sefton, “Implantable Pumps,” in CRC Crit. Rev.Biomed. Eng. 14(3):201-240 (1987); Buchwald et al., “Long-term,Continuous Intravenous Heparin Administration by an Implantable InfusionPump in Ambulatory Patients with Recurrent Venous Thrombosis,” Surgery88:507-516 (1980); and Saudek et al., “A Preliminary Trial of theProgrammable Implantable Medication System for Insulin Delivery,” NewEngl. J. Med. 321:574-579 (1989)). In another embodiment, polymericmaterials can be used (see Goodson; Smolen et al., “Drug Product Designand Performance,” Controlled Drug Bioavailability Vol. 1, John Wiley andSons, New York (1984); Langer et al., “Chemical and Physical Structureof Polymers as Carriers for Controlled Release of Bioactive Agents: AReview,” J. Macromol. Sci. Rev. Macromol. Chem. C23(1):61-126 (1983);Levy et al., “Inhibition of Calcification of Bioprosthetic Heart Valvesby Local Controlled-Release Diphosphonate,” Science 228:190-192 (1985);During et al., “Controlled Release of Dopamine from a Polymeric BrainImplant: In Vivo Characterization,” Ann. Neurol. 25:351-356 (1989); andHoward et al., “Intracerebral drug delivery in rats with lesion-inducedmemory deficits,” J. Neurosurg. 71:105-112 (1989)). In yet anotherembodiment, a controlled- or sustained-release system can be placed inproximity of a target of a Substituted Benzimidazole-Type PiperidineCompound, e.g., the spinal column, brain, or gastrointestinal tract,thus requiring only a fraction of the systemic dose.

The compositions can optionally, but preferably, further comprise asuitable amount of a pharmaceutically acceptable excipient so as toprovide the form for proper administration to the animal. Such apharmaceutical excipient can be a diluent, suspending agent,solubilizer, binder, disintegrant, preservative, coloring agent,lubricant, and the like. The pharmaceutical excipient can be a liquid,such as water or an oil, including those of petroleum, animal,vegetable, or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil, and the like. The pharmaceutical excipient can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In oneembodiment, the pharmaceutically acceptable excipient is sterile whenadministered to an animal. Water is a particularly useful excipient whena Substituted Benzimidazole-Type Piperidine Compound is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid excipients, particularly forinjectable solutions. Suitable pharmaceutical excipients also includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene glycol, water, EtOH, andthe like. The compositions, if desired, can also contain minor amountsof wetting or emulsifying agents, or pH buffering agents. Specificexamples of pharmaceutically acceptable carriers and excipients that canbe used to formulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, (Amer. Pharmaceutical Ass'n, Washington,D.C., 1986), incorporated herein by reference.

The compositions can take the form of solutions, suspensions, emulsions,tablets, pills, pellets, capsules, capsules containing liquids, powders,sustained-release formulations, suppositories, emulsions, aerosols,sprays, suspensions, or any other form suitable for use. In oneembodiment, the composition is in the form of a capsule (see, e.g., U.S.Pat. No. 5,698,155). Other examples of suitable pharmaceuticalexcipients are described by Radebough et al., “Preformulation,” pp.1447-1676 in Remington's Pharmaceutical Sciences Vol. 2 (Gennaro, ed.,19^(th) Ed., Mack Publishing, Easton, Pa., 1995), incorporated herein byreference.

In one embodiment, the Substituted Benzimidazole-Type PiperidineCompounds are formulated in accordance with routine procedures as acomposition adapted for oral administration to human beings. AnSubstituted Benzimidazole-Type Piperidine Compound to be orallydelivered can be in the form of tablets, capsules, gelcaps, caplets,lozenges, aqueous or oily solutions, suspensions, granules, powders,emulsions, syrups, or elixirs, for example. When a SubstitutedBenzimidazole-Type Piperidine Compound is incorporated into oraltablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Techniques and compositions for making solid oraldosage forms are described in Pharmaceutical Dosage Forms: Tablets(Lieberman et al., eds., 2^(nd) Ed., Marcel Dekker, Inc., 1989 and1990). Techniques and compositions for making tablets (compressed andmolded), capsules (hard and soft gelatin) and pills are also describedby King, “Tablets, Capsules, and Pills,” pp. 1553-1593 in Remington'sPharmaceutical Sciences (Osol, ed., 16^(th) Ed., Mack Publishing,Easton, Pa., 1980).

Liquid oral dosage forms include aqueous and nonaqueous solutions,emulsions, suspensions, and solutions and/or suspensions reconstitutedfrom non-effervescent granules, optionally containing one or moresuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, flavoring agents, and the like.Techniques and composition for making liquid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman etal., eds., 2^(nd) Ed., Marcel Dekker, Inc., 1996 and 1998).

When a Substituted Benzimidazole-Type Piperidine Compound is to beinjected parenterally, it can be, e.g., in the form of an isotonicsterile solution. Alternatively, when a Substituted Benzimidazole-TypePiperidine Compound is to be inhaled, it can be formulated into a dryaerosol or can be formulated into an aqueous or partially aqueoussolution.

An orally administered Substituted Benzimidazole-Type PiperidineCompound can contain one or more agents, for example, sweetening agentssuch as fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions can be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compositions.In these latter platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound, which swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time-delay materialsuch as glycerol monostearate or glycerol stearate can also be used.Oral compositions can include standard excipients such as mannitol,lactose, starch, magnesium stearate, sodium saccharin, cellulose, andmagnesium carbonate. In one embodiment, the excipients are ofpharmaceutical grade.

In another embodiment, the Substituted Benzimidazole-Type PiperidineCompounds can be formulated for intravenous administration. In certainembodiments, compositions for intravenous administration comprisesterile isotonic aqueous buffer. Where necessary, the compositions canalso include a solubilizing agent. An Substituted Benzimidazole-TypePiperidine Compound for intravenous administration can optionallyinclude a local anesthetic such as benzocaine or prilocalne to lessenpain at the site of the injection. Generally, the ingredients aresupplied either separately or mixed together in unit dosage form, forexample, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampule or sachette indicatingthe quantity of active agent. Where a Substituted Benzimidazole-TypePiperidine Compound is to be administered by infusion, it can bedispensed, for example, with an infusion bottle containing sterilepharmaceutical grade water or saline. Where a SubstitutedBenzimidazole-Type Piperidine Compound is administered by injection, anampule of sterile water for injection or saline can be provided so thatthe ingredients can be mixed prior to administration.

An Substituted Benzimidazole-Type Piperidine Compound can beadministered by controlled-release or sustained-release means or bydelivery devices that are known to those in the art. Examples include,but are not limited to, those described in U.S. Pat. Nos. 3,845,770,3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595,5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566,each of which is incorporated herein by reference. Such dosage forms canbe used to provide controlled- or sustained-release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,ethylcellulose, other polymer matrices, gels, permeable membranes,osmotic systems, multilayer coatings, microparticles, multiparticulates,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled- orsustained-release formulations known to those in the art, includingthose described herein, can be readily selected for use with the activeingredients of the disclosure. The disclosure thus encompasses singleunit dosage forms suitable for oral administration such as, but notlimited to, tablets, capsules, gelcaps, and caplets that are adapted forcontrolled- or sustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained-release counterparts. In one embodiment,a controlled- or sustained-release composition comprises a minimalamount of a Substituted Benzimidazole-Type Piperidine Compound to treator prevent the Condition or a symptom thereof in a minimum amount oftime. Advantages of controlled- or sustained-release compositionsinclude extended activity of the drug, reduced dosage frequency, andincreased compliance. In addition, controlled- or sustained-releasecompositions can favorably affect the time of onset of action or othercharacteristics, such as blood levels of the SubstitutedBenzimidazole-Type Piperidine Compound, and can thus reduce theoccurrence of adverse side effects.

Controlled- or sustained-release compositions can initially release anamount of a Substituted Benzimidazole-Type Piperidine Compound thatpromptly produces the desired therapeutic or prophylactic effect, andgradually and continually release other amounts of the SubstitutedBenzimidazole-Type Piperidine Compound to maintain this level oftherapeutic or prophylactic effect over an extended period of time. Tomaintain a constant level of the Substituted Benzimidazole-TypePiperidine Compound in the body, the Substituted Benzimidazole-TypePiperidine Compound can be released from the dosage form at a rate thatwill replace the amount of Substituted Benzimidazole-Type PiperidineCompound being metabolized and excreted from the body. Controlled- orsustained-release of an active ingredient can be stimulated by variousconditions, including but not limited to, changes in pH, changes intemperature, concentration or availability of enzymes, concentration oravailability of water, or other physiological conditions or compounds.

The amount of the Substituted Benzimidazole-Type Piperidine Compoundthat is effective for the treatment or prevention of a Condition can bedetermined by standard clinical techniques. In addition, in vitro and/orin vivo assays can optionally be employed to help identify optimaldosage ranges. The precise dose to be employed will also depend on,e.g., the route of administration and the seriousness of the Condition,and can be decided according to the judgment of a practitioner and/oreach animal's circumstances. In other examples thereof, variations willnecessarily occur depending upon the weight and physical condition(e.g., hepatic and renal function) of the animal being treated, theaffliction to be treated, the severity of the symptoms, the frequency ofthe dosage interval, the presence of any deleterious side-effects, andthe particular compound utilized, among other things.

Suitable effective dosage amounts, however, range from about 0.01 mg/kgof body weight to about 3000 mg/kg of body weight of the animal per day,although they are, in certain embodiments, from about 0.01 mg/kg of bodyweight to about 2500 mg/kg of body weight of the animal per day or fromabout 0.01 mg/kg of body weight to about 1000 mg/kg of body weight ofthe animal per day. In another embodiment, the effective dosage amountis about 100 mg/kg of body weight of the animal per day or less. Inanother embodiment, the effective dosage amount ranges from about 0.01mg/kg of body weight to about 100 mg/kg of body weight of the animal perday of a Substituted Benzimidazole-Type Piperidine Compound, in anotherembodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of bodyweight of the animal per day, and in another embodiment, about 0.025mg/kg of body weight to about 20 mg/kg of body weight of the animal perday.

Administration can be as a single dose or as a divided dose. In oneembodiment, an effective dosage amount is administered about every 24 hruntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 hr until the Condition isabated. In another embodiment, an effective dosage amount isadministered about every 8 hr until the Condition is abated. In anotherembodiment, an effective dosage amount is administered about every 6 hruntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 4 hr until the Condition isabated. The effective dosage amounts described herein refer to totalamounts administered; that is, if more than one SubstitutedBenzimidazole-Type Piperidine Compound is administered, the effectivedosage amounts correspond to the total amount administered.

Where a cell capable of expressing the ORL-1 receptor, the g-opioidreceptor, the κ-opioid receptor and/or the δ-opioid receptor iscontacted with a Substituted Benzimidazole-Type Piperidine Compound invitro, the amount effective for inhibiting or activating that receptorfunction in a cell will, in certain embodiments, range from about 10⁻¹²mol/L to about 10⁻⁴ mol/L, in one embodiment, from about 10⁻¹² mol/L toabout 10⁻⁵ mol/L, in another embodiment, from about 10⁻¹² mol/L to about10⁻⁶ mol/L, and in another embodiment, from about 10⁻¹² mol/L to about10⁻⁹ mol/L of a solution or suspension of a pharmaceutically acceptablecarrier or excipient. In one embodiment, the volume of solution orsuspension comprising the Substituted Benzimidazole-Type PiperidineCompound will be from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension will be about 200 μL.

An Substituted Benzimidazole-Type Piperidine Compound has a bindingaffinity (K_(i)) for the human ORL-1 receptor of about 1000 nM or lessin one embodiment, or about 500 nM or less in another embodiment, about100 nM or less in another embodiment, about 50 nM or less in anotherembodiment, or about 20 nM or less in another embodiment, or about 5 nMor less in another embodiment. The binding affinity K_(i) can bemeasured in ways known to the art, e.g., by an assay utilizing membranesfrom recombinant HEK-293 cells expressing the ORL-1 receptor.

In certain embodiments, a Substituted Benzimidazole-Type PiperidineCompound has a Ki (nM) of about 300 or less for binding to ORL-1receptors. In one embodiment, a Substituted Benzimidazole-TypePiperidine Compound of the disclosure has a K_(i) (nM) of about 100 orless. In another embodiment, a Substituted Benzimidazole-Type PiperidineCompound of the disclosure has a K_(i) (nM) of about 35 or less. Inanother embodiment, a Substituted Benzimidazole-Type Piperidine Compoundof the disclosure has a K_(i) (nM) of about 20 or less. In anotherembodiment, a Substituted Benzimidazole-Type Piperidine Compound of thedisclosure has a K_(i) (nM) of about 15 or less. In another embodiment,a Substituted Benzimidazole-Type Piperidine Compound of the disclosurehas a K_(i) (nM) of about 10 or less. In another embodiment, aSubstituted Benzimidazole-Type Piperidine Compound of the disclosure hasa K_(i) (nM) of about 4 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has a K_(i)(nM) of about 1 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has a K_(i)(nM) of about 0.4 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has a K_(i)(nM) of about 0.1 or less.

ORL-1 GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at an ORL-1 receptor. In oneembodiment, a Substituted Benzimidazole-Type Piperidine Compound has anORL-1 GTP EC₅₀ (nM) of about 5000 or less to stimulate ORL-1 receptorfunction. In another embodiment, a Substituted Benzimidazole-TypePiperidine Compound of the disclosure has an ORL-1 GTP EC₅₀ (nM) ofabout 1000 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has an ORL-1GTP EC₅₀ (nM) of about 100 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has an ORL-1GTP EC₅₀ (nM) of about 80 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has an ORL-1GTP EC₅₀ (nM) of about 50 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has an ORL-1GTP EC₅₀ (nM) of about 35 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has an ORL-1GTP EC₅₀ (nM) of about 15 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 10 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 4 or less. In another embodiment, a Substituted Benzimidazole-TypePiperidine Compound has an ORL-1 GTP EC₅₀ (nM) of about 1 or less. Inanother embodiment, a Substituted Benzimidazole-Type Piperidine Compoundhas an ORL-1 GTP EC₅₀ (nM) of about 0.4 or less. In another embodiment,a Substituted Benzimidazole-Type Piperidine Compound has an ORL-1 GTPEC₅₀ (nM) of about 0.1 or less.

ORL-1 GTP Emax (%) is the maximal effect elicited by a compound relativeto the effect elicited by nociceptin, a standard ORL-1 agonist. Incertain embodiments, a Substituted Benzimidazole-Type PiperidineCompound of the disclosure acting as an agonist has an ORL-1 GTP Emax(%) of about 50% or greater. In one embodiment, agonist SubstitutedBenzimidazole-Type Piperidine Compounds has an ORL-1 GTP Emax (%) ofabout 75% or greater. In another embodiment, agonist SubstitutedBenzimidazole-Type Piperidine Compounds has an ORL-1 GTP Emax (%) ofabout 85% or greater. In another embodiment, agonist SubstitutedBenzimidazole-Type Piperidine Compounds has an ORL-1 GTP Emax (%) ofabout 95% or greater. In another embodiment, agonist SubstitutedBenzimidazole-Type Piperidine Compounds has an ORL-1 GTP Emax (%) ofabout 100% or greater. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure acting as apartial agonist has an ORL-1 GTP Emax (%) of less than about 10%. In oneembodiment, partial agonist Substituted Benzimidazole-Type PiperidineCompounds has an ORL-1 GTP Emax (%) of less than about 20%. In anotherembodiment, partial agonist Substituted Benzimidazole-Type PiperidineCompounds has an ORL-1 GTP Emax (%) of less than about 30%. In anotherembodiment, partial agonist Substituted Benzimidazole-Type PiperidineCompounds has an ORL-1 GTP Emax (%) of less than about 40%. In anotherembodiment, partial agonist Substituted Benzimidazole-Type PiperidineCompounds has an ORL-1 GTP Emax (%) of less than about 50%.

In certain embodiments, a Substituted Benzimidazole-Type PiperidineCompound has a binding affinity (K_(i)) for the human μ-opioid receptorof about 1000 nM or less in one embodiment, or about 500 nM or less inanother embodiment, about 100 nM or less in another embodiment, about 50nM or less in another embodiment, or about 20 nM or less in anotherembodiment, or about 5 nM or less in another embodiment.

In certain embodiments, a Substituted Benzimidazole-Type PiperidineCompound has a K_(i) (nM) for the human μ-opioid receptor of about 3000or less for binding to a human μ-opioid receptor, or about 1000 or less,or about 650 or less, or about 525 or less, or about 250 or less, orabout 100 or less, or about 10 or less, or about 1 or less. In oneembodiment, a Substituted Benzimidazole-Type Piperidine Compound hassubstantially no activity.

μ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a human μ-opioid receptor. Incertain embodiments, a Substituted Benzimidazole-Type PiperidineCompound has a μ GTP EC₅₀ (nM) of about 20,000 or less to stimulatehuman μ-opioid receptor function, or about 10,000 or less. In otherembodiments, a Substituted Benzimidazole-Type Piperidine Compound has atμ GTP EC₅₀ (nM) of about 5000 or less to stimulate human μ-opioidreceptor function, or about 4100 or less, or about 3100 or less, orabout 2000 or less, or about 1000 or less, or about 100 or less, orabout 10 or less, or about 1 or less, or about 0.4 or less.

μ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by DAMGO, a standard μ agonist. In certainembodiments, a Substituted Benzimidazole-Type Piperidine Compound has aμ GTP Emax (%) of about 10% or greater, or about 20% or greater, orabout 50% or greater, or about 65% or greater, or about 75% or greater,or about 88% or greater. In other embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a μ GTP Emax (%) of about 10%or less, or about 5% or less, or about 2% or less.

In one embodiment, a Substituted Benzimidazole-Type Piperidine Compoundhas a K_(i) (nM) of about 20,000 or less for binding to a human κ-opioidreceptor. In another embodiment, a Substituted Benzimidazole-TypePiperidine Compound has substantially no activity. In certainembodiments, a Substituted Benzimidazole-Type Piperidine Compound thatbind to the human κ-opioid receptor has a K_(i) (nM) of about 10,000 orless, or about 5000 or less, or about 1000 or less, or about 500 orless, or about 300 or less, or about 100 or less, or about 50 or less,or about 20 or less, or about 15 or less.

κ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a human κ-opioid receptor. Incertain embodiments, a Substituted Benzimidazole-Type PiperidineCompound has a κ GTP EC₅₀ (nM) of about 20,000 or less to stimulatehuman κ-opioid receptor function, or about 10,000 or less, or about 5000or less, or about 2000 or less, or about 1500 or less, or about 800 orless, or about 500 or less, or about 300 or less, or about 100 or less,or about 50 or less, or about 25 or less.

κ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by U69,593. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a κ GTP Emax (%) of about 10%or greater, or about 15% or greater, or about 30% or greater, or about40% or greater, or about 45% or greater, or about 75% or greater, orabout 90% or greater. In other embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a κ GTP Emax (%) of about 10%or less, or about 5% or less, or about 2% or less.

In one embodiment, a Substituted Benzimidazole-Type Piperidine Compoundhas a K_(i) (nM) of about 20,000 or less for binding to a human δ-opioidreceptor. In another embodiment, a Substituted Benzimidazole-TypePiperidine Compound has substantially no activity. In other embodiments,a Substituted Benzimidazole-Type Piperidine Compound that binds to thehuman δ-opioid receptor has a K_(i) (nM) of about 10,000 or less, orabout 9000 or less, or about 7500 or less, or about 6500 or less, orabout 5000 or less, or about 3000 or less, or about 2500 or less, orabout 1000 or less, or about 500 or less, or about 350 or less, or about250 or less, or about 100 or less.

δ GTP EC₅₀ is the concentration of a compound providing 50% of themaximal response for the compound at a human δ-opioid receptor. Incertain embodiments, a Substituted Benzimidazole-Type PiperidineCompound has a 8 GTP EC₅₀ (nM) of about 20,000 or less to stimulatehuman δ-opioid receptor function, or about 10,000 or less, or about 1000or less, or about 100 or less, or about 90 or less, or about 50 or less,or about 25 or less or less.

δ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by met-enkephalin. In certain embodiments, aSubstituted Benzimidazole-Type Piperidine Compound has a δ GTP Emax (%)of about 10% or greater, or about 30% or greater, or about 50% orgreater, or about 75% or greater, or about 90% or greater, or about 100%or greater. In other embodiments, a Substituted Benzimidazole-TypePiperidine Compound has a δ GTP Emax (%) of about 10% or less, or about5% or less, or about 2% or less.

The Substituted Benzimidazole-Type Piperidine Compounds can be assayedin vitro or in vivo for the desired therapeutic or prophylactic activityprior to use in humans. Animal model systems can be used to demonstratesafety and efficacy.

The methods for treating or preventing a Condition in an animal in needthereof can further comprise co-administering to the animal beingadministered a Substituted Benzimidazole-Type Piperidine Compound (i.e.,a first therapeutic agent) a second therapeutic agent. In oneembodiment, the second therapeutic agent is administered in an effectiveamount.

An effective amount of the second therapeutic agent will be known tothose skilled the art depending on the agent. However, it is well withinthe skilled artisan's purview to determine the second therapeuticagent's optimal effective-amount range. An SubstitutedBenzimidazole-Type Piperidine Compound and the second therapeutic agentcombined can act either additively or synergistically to treat the sameCondition, or they may act independently of each other such that theSubstituted Benzimidazole-Type Piperidine Compound treats or prevents afirst Condition and the second therapeutic agent treats or prevents asecond disorder, which can be the same as the first Condition or anotherdisorder. In one embodiment of the disclosure, where a secondtherapeutic agent is administered to an animal for treatment of aCondition (e.g., pain), the minimal effective amount of the SubstitutedBenzimidazole-Type Piperidine Compound will be less than its minimaleffective amount would be where the second therapeutic agent is notadministered. In this embodiment, the Substituted Benzimidazole-TypePiperidine Compound and the second therapeutic agent can actsynergistically to treat or prevent a Condition. In one embodiment, aSubstituted Benzimidazole-Type Piperidine Compound is administeredconcurrently with a second therapeutic agent as a single compositioncomprising an effective amount of a Substituted Benzimidazole-TypePiperidine Compound and an effective amount of the second therapeuticagent. Alternatively, a composition comprising an effective amount of aSubstituted Benzimidazole-Type Piperidine Compound and a secondcomposition comprising an effective amount of the second therapeuticagent are concurrently administered. In another embodiment, an effectiveamount of a Substituted Benzimidazole-Type Piperidine Compound isadministered prior or subsequent to administration of an effectiveamount of the second therapeutic agent. In this embodiment, theSubstituted Benzimidazole-Type Piperidine Compound is administered whilethe second therapeutic agent exerts its therapeutic effect, or thesecond therapeutic agent is administered while the SubstitutedBenzimidazole-Type Piperidine Compound exerts its therapeutic effect fortreating or preventing a Condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-II inhibitor, a 5-lipoxygenaseinhibitor, an anti-emetic, a f3-adrenergic blocker, an anticonvulsant,an antidepressant, a Ca²⁺-channel blocker, an anti-cancer agent, anagent for treating or preventing UI, an agent for treating or preventinganxiety, an agent for treating or preventing a memory disorder, an agentfor treating or preventing obesity, an agent for treating or preventingconstipation, an agent for treating or preventing cough, an agent fortreating or preventing diarrhea, an agent for treating or preventinghigh blood pressure, an agent for treating or preventing epilepsy, anagent for treating or preventing anorexia/cachexia, an agent fortreating or preventing drug abuse, an agent for treating or preventingan ulcer, an agent for treating or preventing IBD, an agent for treatingor preventing IBS, an agent for treating or preventing addictivedisorder, an agent for treating or preventing Parkinson's disease andparkinsonism, an agent for treating or preventing a stroke, an agent fortreating or preventing a seizure, an agent for treating or preventing apruritic condition, an agent for treating or preventing psychosis, anagent for treating or preventing Huntington's chorea, an agent fortreating or preventing ALS, an agent for treating or preventing acognitive disorder, an agent for treating or preventing a migraine, anagent for inhibiting vomiting, an agent for treating or preventingdyskinesia, an agent for treating or preventing depression, or anymixture thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts or solvates thereof, or anymixture thereof.

In certain embodiments, the opioid agonist is codeine, hydromorphone,hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine,tramadol, oxymorphone, pharmaceutically acceptable salts or solvatesthereof, or any mixture thereof.

Examples of useful non-opioid analgesics include, but are not limitedto, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,a pharmaceutically acceptable salt thereof, or any mixture thereof.Other suitable non-opioid analgesics include the following,non-limiting, chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs; salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);alkanones, including nabumetone; a pharmaceutically acceptable saltthereof; or any mixture thereof. For a more detailed description of theNSAIDs, see Insel, “Analgesic-Antipyretic and Anti-inflammatory Agentsand Drugs Employed in the Treatment of Gout,” pp. 617-657 in Goodman andGilman's The Pharmacological Basis of Therapeutics (Goodman et al.,eds., 9^(th) Ed., McGraw-Hill, New York 1996), and Hanson, “Analgesic,Antipyretic and Anti-Inflammatory Drugs,” pp. 1196-1221 in Remington:The Science and Practice of Pharmacy Vol. II (Gennaro, ed., 19^(th) Ed.,Mack Publishing, Easton, Pa., 1995), which are hereby incorporated byreference in their entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, celecoxib,DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone,nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522,RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367,SC-5766, PD-164387, etoricoxib, valdecoxib, parecoxib, apharmaceutically acceptable salt thereof, or any mixture thereof.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, a pharmaceutically acceptable salt thereof, or any mixturethereof.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin,zonisamide, a pharmaceutically acceptable salt thereof, or any mixturethereof.

Examples of useful Ca²⁺-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, perhexyline, a pharmaceuticallyacceptable salt thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, dicyclomine, a pharmaceutically acceptable salt thereof, orany mixture thereof.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, tonazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; propanediolcarbamates, such as meprobamate and tybamate; a pharmaceuticallyacceptable salt thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingdiarrhea include, but are not limited to, diphenoxylate, loperamide, apharmaceutically acceptable salt thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, γ vinyl GABA, acetazolamide,felbamate, a pharmaceutically acceptable salt thereof, or any mixturethereof.

Examples of useful therapeutic agents for treating or preventing drugabuse include, but are not limited to, methadone, desipramine,amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, serotoninantagonists, a pharmaceutically acceptable salt thereof, or any mixturethereof.

Examples of non-steroidal anti-inflammatory agents, 5-lipoxygenaseinhibitors, anti-emetics, β-adrenergic blockers, antidepressants, andanti-cancer agents are known in the art and can be selected by thoseskilled in the art. Examples of useful therapeutic agents for treatingor preventing memory disorder, obesity, constipation, cough, high bloodpressure, anorexia/cachexia, an ulcer, IBD, IBS, addictive disorder,Parkinson's disease and parkinsonism, a stroke, a seizure, a pruriticcondition, psychosis, Huntington's chorea, ALS, a cognitive disorder, amigraine, dyskinesia, depression, and/or treating, preventing orinhibiting vomiting include those that are known in the art and can beselected by those skilled in the art.

A composition of the disclosure is prepared by a method comprisingadmixing a Substituted Benzimidazole-Type Piperidine Compound or apharmaceutically acceptable salt or solvate thereof with apharmaceutically acceptable carrier or excipient. Admixing can beaccomplished using methods known for admixing a compound (or derivative)and a pharmaceutically acceptable carrier or excipient. In oneembodiment, the Substituted Benzimidazole-Type Piperidine Compound ispresent in the composition in an effective amount.

4.8 Kits

The disclosure further provides kits that can simplify the handling andadministration of a Substituted Benzimidazole-Type Piperidine Compoundto an animal.

A typical kit of the disclosure comprises a unit dosage form of aSubstituted Benzimidazole-Type Piperidine Compound. In one embodiment,the unit dosage form comprises a first container, which can be sterile,containing an effective amount of a Substituted Benzimidazole-TypePiperidine Compound and a pharmaceutically acceptable carrier orexcipient. The kit can further comprise a label or printed instructionsinstructing the use of the Substituted Benzimidazole-Type PiperidineCompound to treat or prevent a Condition. The kit can further comprise aunit dosage form of a second therapeutic agent, for example, a secondcontainer containing an effective amount of the second therapeutic agentand a pharmaceutically acceptable carrier or excipient. In anotherembodiment, the kit comprises a container containing an effective amountof a Substituted Benzimidazole-Type Piperidine Compound, an effectiveamount of a second therapeutic agent and a pharmaceutically acceptablecarrier or excipient. Examples of second therapeutic agents include, butare not limited to, those listed above.

Kits of the disclosure can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, that would be within the purview of those skilled inthe art, and changes in formulation or changes in experimental design,are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

Certain Examples below relate to the synthesis of illustrativeSubstituted Benzimidazole-Type Piperidine Compounds.

5.1 Example 1 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds ZA01-ZA03 and H30b(i)

Compound 66,N¹-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)benzene-1,2-diamine,was prepared as described in Example 6.

To a solution of Compound 66 (0.57 g, 1.57 mmol) and((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (Compound 30,0.44 g, 2.04 mmol, Sigma-Aldrich, St. Louis, Mo.) in DCM (10 mL) at atemperature of about 25° C. was added HOBT (0.35 g, 2.59 mmol,Sigma-Aldrich), EDCI hydrochloride (0.50 g, 2.59 mmol, Sigma-Aldrich),and DIEA (0.70 mL, Sigma-Aldrich). The resulting reaction mixture wasstirred at that temperature for 16 hrs. Thereafter, the mixture wasquenched with water and extracted twice with DCM (50 mL for eachextraction). The organic portions were combined, dried (over Na₂SO₄),and evaporated to dryness under reduced pressure to provide Compound 31,(S)-tert-butyl2-((2-(((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)amino)phenyl)carbamoyl)pyrrolidine-1-carboxylate.

The identity of Compound 31 was confirmed using MS.

Compound 31: MS: m/z=565.4 [M+H]⁺.

To a solution of Compound 31 (1.57 mmol) in toluene (15 mL) at atemperature of about 25° C. was added AcOH (0.45 mL) The resultingreaction mixture was heated to 100° C. and stirred at that temperaturefor 16 hrs. Thereafter, the mixture was cooled to a temperature of about25° C., quenched with water, and extracted twice with DCM (50 mL foreach extraction). The organic portions were combined, washed with anaqueous NaHCO₃ solution, dried (over Na₂SO₄), and evaporated to drynessunder reduced pressure to provide a product which was chromatographed ona flash column eluted with a gradient of from 0:100 MeOH:DCM to 10:90MeOH:DCM. The fractions containing the product were combined and, underreduced pressure, evaporated and dried to provide SubstitutedBenzimidazole-Type Piperidine Compound ZA01, (S)-tert-butyl2-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(80% yield from Compound 66).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA01was confirmed using MS.

Substituted Benzimidazole-Type Piperidine Compound ZA01: MS: m/z=547.4[M+H]⁺.

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA01(1.5 mmol) in MeOH (3 mL) at a temperature of about 25° C. was added 4mol/L HCl in 1,4-dioxane (3 mL). The resulting reaction mixture wasstirred at that temperature for 2 hrs then evaporated to dryness underreduced pressure. To the residue was added an aqueous NaHCO₃ solution(50 mL). The resulting mixture was extracted twice with DCM (50 mL foreach extraction). The organic portions were combined, washed with brine,dried (over Na₂SO₄), and evaporated to dryness under reduced pressure toprovide a product which was chromatographed on a flash column elutedwith a gradient of from 0:100 MeOH (10% NH₄OH):DCM to 30:70 MeOH (10%NH₄OH):DCM. The fractions containing the product were combined and,under reduced pressure, evaporated and dried to provide SubstitutedBenzimidazole-Type Piperidine Compound ZA02,1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazole(yield 95%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA02was confirmed using MS.

Substituted Benzimidazole-Type Piperidine Compound ZA02: MS: m/z=447.4[M+H]⁺.

An alkylation reaction was performed as follows. To a solution ofSubstituted Benzimidazole-Type Piperidine Compound ZA02 (0.50 mmol) andmethyl 2-bromoacetate (0.75 mmol, Sigma-Aldrich) in DMF (2 mL) at atemperature of about 25° C. was added DIEA (2.0 mmol). The resultingreaction mixture was heated to 45° C. and stirred at that temperaturefor 2 hrs. Thereafter, the mixture was evaporated to dryness underreduced pressure to provide a product which was chromatographed on aflash column eluted with a gradient of from 0:100 MeOH:DCM to 10:90MeOH:DCM to provide Substituted Benzimidazole-Type Piperidine CompoundZA03, methyl2-((S)-2-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)acetate(yield 80%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA03was confirmed using MS.

Substituted Benzimidazole-Type Piperidine Compound ZA03: MS: m/z=519.4[M+H]⁺.

An alternate alkylation reaction was performed as follows. To a solutionof Substituted Benzimidazole-Type Piperidine Compound ZA02 (0.50 mmol)and methyl 2-bromoacetate (0.75 mmol) in DMF (2 mL) at a temperature ofabout 25° C. was added K₂CO₃ (2.0 mmol). The resulting reaction mixturewas heated to 85° C. and stirred at that temperature for 1.5 hrs.Thereafter, the mixture was evaporated to dryness under reduced pressureto provide a product which was chromatographed on a flash column elutedwith a gradient of from 0:100 MeOH:DCM to 10:90 MeOH:DCM to provideSubstituted Benzimidazole-Type Piperidine Compound ZA03 (yield 50%).

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA03(0.37 mmol) in MeOH (2.0 mL) at a temperature of about 25° C. was added1 mol/L NaOH (0.5 mmol, 0.5 mL) solution. The resulting reaction mixturewas stirred at that temperature for 1.5 hrs. Thereafter, the mixture wasevaporated to dryness under reduced pressure to provide a residue. Waterwas added to the residue, the resulting mixture was acidified with 1mol/L HCl to a pH of about 4.0, and the mixture was evaporated todryness under reduced pressure to provide a product which waschromatographed on a flash column eluted with a gradient of from 0:100MeOH (10% NH₄OH):DCM to 30:70 MeOH (10% NH₄OH):DCM. The fractionscontaining the product were combined and, under reduced pressure,evaporated and dried to provide Substituted Benzimidazole-TypePiperidine Compound H30b(i),2-((S)-2-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)aceticacid (yield 75%).

The identity of Substituted Benzimidazole-Type Piperidine CompoundH30b(i) was confirmed using ¹H-NMR and MS.

Substituted Benzimidazole-Type Piperidine Compound H30b(i): ¹H-NMR:δ_(H) (ppm, CD₃OD): 7.66 (m, 2H), 7.30 (m, 2H), 6.48 (br, s, 1H), 4.40(br, s, 1H), 4.18 (br, s, 2H), 3.76 (br, s, 1H), 3.33 (m, 1H), 3.10 (m,2H), 2.61 (m, 4H), 2.46 (m, 6H), 2.07-1.88 (m, 10H), 1.87-1.41 (m, 11H);MS: m/z=505.2 [M+H]⁺.

5.2 Example 2 Synthesis of Substituted Benzimidazole-Type PiperidineCompound H36b(i)

Substituted Benzimidazole-Type Piperidine Compound ZA03 was prepared asdescribed in Example 1 herein.

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA03(0.37 mmol) in MeOH (1.0 mL) at a temperature of about 25° C. was addeda 7 mol/L ammonia solution in MeOH (3.5 mmol, 0.5 mL). The resultingreaction mixture was stirred at that temperature for 24 hrs. Thereafter,the mixture was evaporated to dryness under reduced pressure to providea product which was chromatographed on a flash column eluted with agradient of from 0:100 MeOH (10% NH₄OH):DCM to 30:70 MeOH (10%NH₄OH):DCM. The fractions containing the product were combined and,under reduced pressure, evaporated and dried to provide SubstitutedBenzimidazole-Type Piperidine Compound H36b(i),2-((S)-2-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)acetamide(yield 60%).

The identity of Substituted Benzimidazole-Type Piperidine CompoundH36b(i) was confirmed using ¹H-NMR and MS.

Substituted Benzimidazole-Type Piperidine Compound H36b(i): ¹H-NMR:δ_(H) (ppm, CD₃OD): 7.76 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.28(m, 2H), 5.35 (br, s, 1H), 4.60 (br, s, 1H), 4.11 (m, 1H), 3.67 (br, s,1H), 3.40 (m, 2H), 2.94 (m, 1H), 2.46-2.06 (m, 10H), 2.02-1.52 (m, 15H),1.29 (m, 5H); MS: m/z=504.3 [M+H]⁺.

5.3 Example 3 Synthesis of Substituted Benzimidazole-Type Piperidine

Substituted Benzimidazole-Type Piperidine Compound ZA04,1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-((S)-piperidin-3-yl)-1H-benzo[d]imidazole,was prepared from Compound 66 in a similar manner to thepreviously-described preparation of Compound ZA02 in Example 1 exceptthat (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid(Sigma-Aldrich) was used in place of Compound 30.

Thereafter, in a similar manner to the previously-described preparationof Compound ZA03 in Example 1, the alkylation step was performed. Thisprovided, simultaneously, the major mono-alkylation product SubstitutedBenzimidazole-Type Piperidine Compound ZA05, methyl2-((S)-3-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetate,and the minor di-alkylation product Substituted Benzimidazole-TypePiperidine Compound ZA06, methyl2-((E)-3-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1-(2-methoxy-2-oxoethyl)piperidin-3-ylidene)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate.

In a similar manner to the previously-described preparation of CompoundH30b(i) in Example 1, the hydrolysis step was performed with SubstitutedBenzimidazole-Type Piperidine Compounds ZA05 and ZA06 to provide,simultaneously, Substituted Benzimidazole-Type Piperidine CompoundH56d(ii),2-((S)-3-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)aceticacid and Substituted Benzimidazole-Type Piperidine Compound O85d,2-((E)-3-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1-(carboxymethyl)piperidin-3-ylidene)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)aceticacid, respectively.

The identity of Substituted Benzimidazole-Type Piperidine CompoundH56d(ii) was confirmed using ¹H-NMR and MS.

Substituted Benzimidazole-Type Piperidine Compound H56d(ii): ¹H-NMR:δ_(H) (ppm, CD₃OD): 7.81 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.38(m, 2H), 5.40 (m, 1H), 4.30 (m, 2H), 4.02-3.75 (m, 3H), 3.77 (m, 2H),3.58 (m, 1H), 3.36 (m, 1H), 2.81-2.48 (m, 4H), 2.37 (m, 3H), 2.13-1.60(m, 16H), 1.57-1.38 (m, 5H); MS: m/z=519.3 [M+H]⁺.

The identity of Substituted Benzimidazole-Type Piperidine Compound O85dwas confirmed using ¹H-NMR and MS.

Substituted Benzimidazole-Type Piperidine Compound O85d: ¹H-NMR: δ_(H)(ppm, CD₃OD): 7.80 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.34 (m,2H), 5.56 (br, s, 1H), 4.39 (br, s, 2H), 4.23 (m, 1H), 4.05 (m, 2H),3.85 (m, 1H), 3.60 (m, 1H), 3.44 (m, 1H), 3.19 (m, 1H), 3.03 (m, 2H),2.68 (m, 4H), 2.49 (m, 3H), 2.20-1.75 (m, 16H), 1.56 (m, 5H); MS:m/z=577.2 [M+H]⁺.

5.4 Example 4 Synthesis of Compound 44

2-Adamantanediol (Compound 34, 500 g, 2.97 mol, Sigma-Aldrich), p-tosylchloride (624 g, 3.27 mol, Sigma-Aldrich), and pyridine (1.5 L) werecombined and stirred under an argon atmosphere. The reaction mixture washeated to a temperature in the range of 68-71° C. and remained at thattemperature for 2.5 hrs. The reaction mixture was cooled to atemperature of about 25° C. and poured into saturated brine (6 L). Theresulting mixture was extracted three times with MTBE (4L for eachextraction). The organic portions were combined, dried (over MgSO₄),filtered, and concentrated onto lkg silica gel (pre-treated withhexanes:TEA). The adsorbed material was chromatographed on 1.5 kg silicaeluted sequentially with 1:10 EtOAc:hexanes (5 L) then 2:10EtOAc:hexanes (SL). All product fractions were combined and evaporatedunder reduced pressure to provide a residue. The residue was suspendedin deionized water (2 L), stirred for 10 min, and filtered under reducedpressure to remove any excess reactants. The remaining solids were takenup in MTBE (2 L), dried (over MgSO₄), filtered, and evaporated underreduced pressure to provide 301 g of Compound 35,(1R,5S)-7-methylenebicyclo[3.3.1]nonan-3-one, as a white crystallinesolid (yield 67%).

The identity of Compound 35 was confirmed using ¹H-NMR and TLC.

Compound 35: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 4.79 (2H, s), 2.51(8H, m), 2.29 (2H, m), 1.94 (2H, m), 1.60 (1H, m); TLC (SiO₂) 1:10EtOAc:hexanes: R_(f)=0.25 (visualized with KMnO₄ spray reagent).

Compound 35 (250 g, 1.66 mol) was divided into five equal batches. Undera hydrogen atmosphere, the first batch was hydrogenated over platinumblack (5 g, Sigma-Aldrich) at 50 psi in dry 99:1 cyclohexane:EtOAc (200mL) for 2 hrs. The reaction mixture was decanted and the remainingcatalyst washed with cyclohexane until no product remained as determinedby TLC. The reaction flask was then recharged with the next batch ofCompound 35, cyclohexane (200 mL), and hydrogen and the reaction mixturewas hydrogenated at 50 psi for 2 hrs. This procedure was repeated untilall batches were reacted. All filtrates were combined, filtered throughCELITE, and concentrated at a temperature of about 25° C. to provideCompound 36, 7-methylbicyclo[3.3.1]nonan-3-one, as a colorless oil.

The identity of Compound 36 was confirmed using ¹H-NMR and TLC.

Compound 36: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 2.42 (4H, m), 2.26(2H, m), 1.98-2.00 (3H, m), 1.65 (1H, m), 1.54 (1H, m), 0.80 (1H, m);TLC (SiO₂) 2:10 EtOAc:hexanes: R_(f)=0.30 (visualized with KMnO₄ sprayreagent).

Compound 36, taken directly from the previous step, was taken up in AcOH(1 L). To this was added 50% aqueous NH₂OH (100 mL, Sigma-Aldrich). Withstirring, the reaction mixture was heated to a gentle reflux andrefluxed for 1 hr. The mixture was cooled to a temperature of about 25°C. and slowly poured into 2.5M Na₂CO₃ aqueous solution (5 L) withstirring. Thereafter, the mixture was stirred vigorously for 1 hr.Deionized water (1 L) was added and the mixture was stirred for another0.5 hrs. The precipitate that formed was collected by filtering underreduced pressure and washed with deionized water (2 L). The residue wastaken up in DCM (1 L), dried (over MgSO₄), filtered, and evaporatedunder reduced pressure to provide 231.5 g of Compound 37,7-methylbicyclo[3.3.1]nonan-3-one oxime, as a white fluffy solid (85%yield from Compound 35).

The identity of Compound 37 was confirmed using ¹H-NMR.

Compound 37: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 3.21 (1H, d),2.05-2.41 (4H, m), 1.73-2.11 (4H, m), 1.51-1.73 (2H, m), 1.33 (1H, d),0.82 (4H, m), 0.63 (1H, t).

To a three neck 5L round bottom flask equipped with an overhead stirrer,1 L pressure equalizing dropping funnel, and temperature probe was addedtoluene (about 3 L) and Na metal (67.17 g, 2.8 mol, Sigma-Aldrich).Under an argon atmosphere, the mixture was heated to a gentle refluxuntil the Na metal became molten. A solution of a portion of Compound 37(66.66 g, 0.40 mol) in dry isopropyl alcohol (230 mL) was then addeddropwise via the dropping funnel over 1.5 hrs. With stirring, theresulting reaction mixture was heated to reflux and refluxed for 16 hrs.After cooling to a temperature of about 25° C., the following materialswere added in sequential order: EtOH (164 mL) dropwise over 15 min, 1:1EtOH:H₂O (164 mL) dropwise over 15 min, and water (500 mL) dropwise over30 min. The resulting mixture was stirred for 2 hrs. The mixture waspoured into a 6L separatory funnel and the organic layer was separated.The aqueous portion was extracted three times with Et₂O (1 L for eachextraction).

The process just described was repeated twice more with 66.66 g ofCompound 37 being used each time. All organic portions were combined,dried (over MgSO₄), and filtered into a 6L Erlenmeyer flask. To themixture was added 2M HCl in Et₂O (1.5 L, 2.5 eq). The mixture wasallowed to stir and cool in an ice:MeOH bath for 1 hr. The solids thatformed were filtered under reduced pressure and dried under reducedpressure at 50° C. for 18 hr to provide 100.01 g of Compound 38,(3s,7s)-7-methylbicyclo[3.3.1]nonan-3-amine hydrochloride, as a whitecrystalline solid. The filtrate was evaporated under reduced pressure toprovide a residue which was triturated with Et₂O (2 L). The solids thatremained were filtered and washed with Et₂O (2 L) to provide 87.1 g of asecond crop of Compound 38 after drying (overall yield 39%).

The identity of Compound 38 was confirmed using ¹H-NMR.

Compound 38: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 8.28 (3H, bs), 3.55(1H, m), 2.25 (2H, m), 1.81-2.09 (4H, m), 1.85 (1H, m), 1.61 (3H, m)1.08 (1H, d), 0.70-0.88 (5H, m).

Compound 38 (87.1 g, 0.463 mol),9-benzyl-3-oxo-9-azoniabicyclo[3.3.1]nonane bromide (Compound 39, 165.20g, 0.509 mol, Sigma-Aldrich), potassium carbonate (67.83 g, 0.491 mol),EtOH (1.07 L), and water (346 mL) were combined. The resulting reactionmixture was stirred for about 16 hrs at a temperature of about 25° C.The reaction mixture was then heated to reflux and refluxed for 3 hrs.Thereafter, the mixture was cooled to a temperature of about 25° C. thenfurther cooled to 5° C. in an ice/MeOH bath and allowed to stir for 30min at that temperature. The solids that formed were filtered underreduced pressure, washed with deionized water, and dried under reducedpressure to provide 102.1 g of Compound 40,(1R,3r,5S,7s)-7-methyl-9′-aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-one, asan off-white crystalline solid (yield 80%).

The identity of Compound 40 was confirmed using ¹H-NMR.

Compound 40: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 3.68 (2H, m), 3.05(1H, m), 2.61 (2H, m), 2.25 (4H, m), 1.98 (1H, m), 1.85 (4H, m),1.49-1.78 (7H, m), 1.25 (2H, m), 1.07 (1H, d), 0.86 (3H, d), 0.78 (2H,t).

Compound 40 (67 g, 0.243 mol), THF (500 mL), and AcOH (41.78 mL, 0.730mol) were combined. To this mixture was added 50% aqueous NH₂OH (45 mL,0.730 mol). With stirring, the resulting reaction mixture was heated toreflux and refluxed for 1 hr. The mixture was cooled to a temperature ofabout 25° C. and deionized water was added (500 mL). Potassium carbonate(100 g, 0.730 mol) in deionized water (500 mL) was then added in oneportion. The resulting mixture was stirred and cooled in an ice bath for1 hr. The solids that formed were filtered under reduced pressure anddried under reduced pressure at 60° C. to provide Compound 41,(1R,3r,5S,7s)-7-methyl-9′-aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-one oxime(yield>99%).

The identity of Compound 41 was confirmed using ¹H-NMR.

Compound 41: ¹H-NMR: δ_(H) (ppm, 400 MHz, CD₃OD): 3.76 (1H, m), 3.45(2H, m), 3.18 (1H, m), 3.02 (1H, m), 2.62 (1H, m), 2.27 (4H, m),1.78-2.08 (7H, m), 1.67 (1H, m), 1.58 (2H, m), 1.46 (1H, m), 1.22 (2H,t), 1.09 (1H, d), 0.85 (5H, m).

Compound 41 (70.01 g, 0.241 mol) was taken up in AcOH (400 mL). Thismixture was divided into two batches. Under a hydrogen atmosphere, toeach batch was added platinum (IV) oxide (5.98 g, 0.2 eq, Sigma-Aldrich)and each batch was then hydrogenated at 50 psi for 16 hrs to 18 hrs. Thebatches were combined and filtered through CELITE. The filter cake waswashed with AcOH (500 mL). The filtrate was concentrated under reducedpressure at 70° C. to provide an oil. To the oil was added MTBE (6 L).The mixture was stirred and cooled to 0° C. for 1 hr. The whiteprecipitate that formed was filtered under reduced pressure, washed withEt₂O (2 L), and dried under reduced pressure to provide 76.2 g ofCompound 42,(1R,1′R,3r,3′R,5S,5′S,7S)-7-methyl-9′-aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-amineacetate, as a white solid (yield 94%).

The identity of Compound 42 was confirmed using ¹H-NMR and LC/MS.

Compound 42: ¹H-NMR: δ_(H) (ppm, 400 MHz, CD₃OD): 3.73 (2H, m), 3.55(1H, m), 2.46 (2H, m), 2.24 (2H, m), 1.75-2.12 (11H, m), 1.45-1.75 (4H,m), 1.28 (4H, m), 1.06 (1H, d), 0.89 (3H, d), 0.80 (2H, t); LC/MS(t_(r)=1.689 min): m/z=277.3 [M+H]⁺ (Calc.: 276.5).

Compound 42 (80.0 g, 0.23 mol), 1-fluoro-2-nitrobenzene (35.69 g, 0.253mol, Sigma-Aldrich), and potassium carbonate (95.36 g, 0.69 mol) werecombined in dry DMF (400 mL). The reaction mixture was heated to 110° C.under an argon atmosphere for 1 hr then cooled to a temperature of about25° C. Deionized water (2 L) was added and the mixture was stirred andcooled in an ice/MeOH bath for 1 hr. The resulting solids were filteredunder reduced pressure, washed with deionized water (4 L), and driedunder reduced pressure to provide 66.81 g of Compound 43,(1R,1′R,3r,3′R,5S,5′S,7S)-7-methyl-N-(2-nitrophenyl)-9′-aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-amine,as a orange solid (yield 73%).

The identity of Compound 43 was confirmed using ¹H-NMR and LC/MS.

Compound 43: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 8.17 (1H, d), 8.01(1H, m), 7.43 (1H, t), 6.93 (1H, d), 6.61 (1H, t), 3.95 (1H, m), 3.45(2H, m), 3.06 (1H, m), 2.48 (2H, m), 2.20 (2H, m), 1.87-2.08 (4H, m),1.45-1.89 (6H, m), 1.35 (2H, t), 0.95-1.22 (5H, m), 0.87 (5H, m); LC/MS(t_(r)=2.732 min): m/z=398.4 [M+H]⁺ (Calc.: 397.6).

Compound 43 (30.0 g, 75.57 mmol) was taken up in DCM (100 mL). Under ahydrogen atmosphere, to this was added Pd/C (3 g) and, with stirring,the reaction mixture was hydrogenated at 50 psi for 2 hr at atemperature of about 25° C. to provide Compound 44,N¹-((1R,1′R,3r,3′R,5S,5′S,7S)-7-methyl-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)benzene-1,2-diamine.

The identity of Compound 44 was confirmed using LC/MS.

Compound 44: LC/MS (t_(r=2.045) min): m/z=368.9 [M+H]⁺ (Calc.: 367.6).

5.5 Example 5 Synthesis of Compound 56

2-Adamantanone (Compound 46, 1000 g, 6.66 mol, Sigma-Aldrich) wasdissolved in TFA (3 L, Sigma-Aldrich). To this mechanically stirredmixture surrounded by a cooling bath with a temperature maintained at20° C. was added sodium percarbonate (1254.8 g, 7.99 mol, Sigma-Aldrich)portion-wise over 1 hr; the temperature of the reaction mixtureincreased to 60° C. during the addition. After 2 hrs additionalstirring, deionized water (4 L) was added followed by four extractionswith DCM (2L for each extraction). The organic portions were combined,dried (over MgSO₄), filtered, and evaporated under reduced pressure toprovide 1180 g of Compound 47,(1R,3r,6s,8S)-4-oxatricyclo[4.3.1.13,8]undecan-5-one, as a whitecrystalline solid (yield 97%).

The identity of Compound 47 was confirmed using ¹H-NMR and TLC.

Compound 47: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 4.48 (1H, s), 3.06(1H, m), 2.09 (2H, m), 2.00 (3H, m), 1.95 (2H, m), 1.81 (2H, m), 1.70(2H, m); TLC (SiO₂) 1:1 EtOAc:hexanes: R_(f)=0.8 (visualized withmolybdenum blue spray reagent).

Compound 47 (1572.7 g, 9.46 mol) was taken up in MeOH (2 L). To this wasadded NaOH (2270 g, 56.7 mol) in deionized water (6 L); the temperatureof the mixture increased from about 25° C. to 54° C. during theaddition. With stirring, the resulting reaction mixture was heated to agentle reflux and refluxed for 36 hrs. After cooling to a temperature ofabout 25° C., the MeOH was removed by vacuum distillation at 60° C. Theresulting solution was stirred and acidified with concentrated HCl to apH of about 2.5. The white precipitate that formed was allowed to stirfor 18 hrs at a temperature of about 25° C. then filtered under reducedpressure to provide partially dried Compound 48,(1R,3r,5S,7r)-7-hydroxybicyclo[3.3.1]nonane-3-carboxylic acid.

The identity of Compound 48 was confirmed using ¹H-NMR and TLC.

Compound 48: ¹H-NMR: δ_(H) (ppm, 400 MHz, d6-DMSO): 11.88 (1H, s), 4.44(1H, s), 3.73 (1H, m), 1.95 (4H, m), 1.63 (2H, m), 1.41 (3H, m), 1.22(2H, m), 1.16 (1H, m); TLC (SiO₂) 2:1:0.1 EtOAc:hexanes:AcOH: R_(f)=0.3(visualized with molybdenum blue spray reagent).

Compound 48, taken directly from the previous step, was suspended intoluene (8 L). To this was added methane sulfonic acid (367 mL, 4.73mol, Sigma-Aldrich). With stirring, the resulting reaction mixture washeated to reflux and water removed azeotropically for 5 hrs. Aftercooling to a temperature of about 25° C., deionized water (4 L) wasadded with stirring. The organic layer was separated, dried (overMgSO₄), filtered, and concentrated to provide Compound 49,(1R,3S,5S)-bicyclo[3.3.1]non-6-ene-3-carboxylic acid.

The identity of Compound 49 was confirmed using ¹H-NMR and TLC.

Compound 49: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 10.45 (1H, bs), 5.85(1H, m), 5.70 (1H, m), 2.79 (1H, m), 2.37 (2H, m), 2.11 (1H, m), 1.81(3H, m), 1.61 (4H, m); TLC (SiO₂) 1:1:0.1 EtOAc:hexanes:AcOH: R_(f)=0.8(visualized with molybdenum blue spray reagent).

Compound 49, taken directly from the previous step, was taken up in MeOH(1 L). This was divided into six batches and to each, under a hydrogenatmosphere, was added 10% Pd/C (0.01 mol). The reaction mixtures wereeach hydrogenated at 50 psi until hydrogen uptake ceased (10 hrs to 15hrs). The mixtures were combined, filtered through CELITE, and NaOH (1kg) in deionized water (400 mL) was added. The mixture was stirred for 4h at a temperature of about 25° C. The mixture was concentrated underreduced pressure and deionized water (4 L) was added. Concentrated HClwas added until a pH within the range of 3-4 was achieved. The whitesolid that formed was allowed to stir for 1 hr at a temperature of about25° C. and then was filtered under reduced pressure to provide 1.232 kgof Compound 50, (1R,3r,5S)-bicyclo[3.3.1]nonane-3-carboxylic acid, as anoff-white crystalline solid (78% yield from Compound 47).

The identity of Compound 50 was confirmed using ¹H-NMR and TLC.

Compound 50: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 9.25 (1H, bs), 3.13(1H, m), 1.97 (4H, m), 1.80 (2H, m), 1.70 (5H, m), 1.57 (3H, m); TLC(SiO₂) 1:1:0.1 EtOAc:hexanes:AcOH: R_(f)=0.8 (visualized with molybdenumblue spray reagent).

Compound 50 (1108.5 g, 6.59 mol) was taken up in toluene (5 L) in a 20Lreaction vessel. To this was added TEA (1013.3 mL, 7.26 mol). Theresulting mixture was stirred and heated to 75° C. under a nitrogenatmosphere. The diphenyl phosphoryl azide (DPPA, 1564 mL, 7.26 mol,Sigma-Aldrich) was diluted with toluene to 2 L total volume and addedslowly via addition funnel over 1.5 hrs; during this addition thetemperature increased by about 10° C. to 15° C. The resulting reactionmixture was allowed to stir for 3 hrs at 75° C. The mixture was thenconcentrated to a brownish-yellow oil by vacuum distillation at 90° C.The oil was cooled to 5° C. and THF (2.5 L) was added. The mixture wasallowed to stir and cool to 0° C. NaOH (792 g, 19.80 mol) in deionizedwater (3 L) was added over 1 hr keeping the temperature below 5° C. Themixture was stirred for 18 hrs at 5° C. The resulting mixture was thenextracted twice with Et₂O (4L for each extraction). To the remainingaqueous mixture at 5° C. was slowly added concentrated HCl until a pH ofabout 6-7 was reached; no significant change in temperature occurredduring this neutralization. The resulting white precipitate was allowedto stir for 2 hrs at 0° C. The precipitate was then filtered underreduced pressure and dried under reduced pressure at 50° C. to provide1.875 kg of Compound 51, (1R,3r,5S)-bicyclo[3.3.1]nonan-3-amine diphenylphosphate salt, as a white solid (yield 73.1%).

The identity of Compound 51 was confirmed using ¹H-NMR.

Compound 51: ¹H-NMR: δ_(H) (ppm, 400 MHz, d6-DMSO): 7.78 (2H, s), 7.22(4H, t), 7.11 (4H, m), 6.93 (2H, t), 3.61 (1H, m), 3.31 (1H, s), 1.93(4H, m), 1.33-1.60 (10H, m).

Compound 51 (1037.5 g, 2.67 mol) and Compound 39 (1000 g, 3.08 mol) weresuspended in EtOH (6.2 L) and deionized water (2 L). To this stirredmixture was added potassium carbonate (390.72 g, 2.83 mol) in deionizedwater (800 mL). The resulting reaction mixture was stirred for 18 hrs ata temperature of about 25° C. The reaction mixture was then heated toreflux, about 81° C., and refluxed for 3 hrs. Thereafter, the mixturewas allowed to cool slowly over 4 h to a temperature of about 25° C.with vigorous stirring during which time a white precipitate formed. Themixture was then cooled to 5° C. and allowed to stir for 2 hrs at thattemperature. The white precipitate was filtered under reduced pressure,washed with deionized water (8 L), and dried under reduced pressure at60° C. to provide 580.1 g of Compound 52,(1R,1′R,3r,5S,5′S)-9′-aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-one, as awhite crystalline solid (yield 83.1%).

The identity of Compound 52 was confirmed using ¹H-NMR and TLC.

Compound 52: ¹H-NMR: δ_(H) (ppm, 400 MHz, CDCl₃): 3.69 (2H, s), 3.38(1H, m), 2.62 (2H, m), 2.21 (2H, d), 2.12 (4H, m), 1.85 (2H, m),1.41-1.78 (14H, m); TLC (SiO₂) 7:3 hexanes:EtOAc:R_(f)=0.4 (visualizedwith potassium iodoplatinate spray).

Compound 52 (580.1 g, 2.22 mol) and THF (4 L) were introduced into areactor; the reactor temperature control was set to 18° C. 50% AqueousNH₂OH (415 mL, 6.66 mol) was added followed by the slow addition of AcOH(381.25 mL, 6.66 mol). The temperature of the reaction mixture increasedto 28° C. during the addition. The reaction mixture was stirred for 16hrs at a temperature of about 25° C. then heated to a gentle reflux andrefluxed for 1 hr. The mixture was cooled to a temperature of about 25°C. and deionized water (4 L) and DCM (4 L) were added. With vigorousstirring, solid NaHCO₃ (560 g, 6.66 mol) was then slowly added over 30min and the mixture was allowed to stir until effervescence ceased. Thewhite precipitate that formed was filtered under reduced pressure,washed with deionized water (1 L), and dried under reduced pressure at60° C. for 72 hrs to provide 432.5 g of Compound 53,(1R,1′R,3r,5S,5′S)-9′-aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-one oxime, asa white solid (yield 70.6%). The filtrate was allowed to form layers andthe organic layer was separated. The aqueous layer was washed threetimes with DCM (2L for each wash). The organic portions were combined,dried (over MgSO₄), filtered, and evaporated under reduced pressure toprovide a pale yellow solid. The solid was triturated with 10:1Et₂O:EtOAc (1 L), stirred for 1 hr, and filtered under reduced pressureto provide a residue which was dried under reduced pressure at 60° C.for 72 hrs to provide an additional 138.4 g of Compound 53 as a whitesolid (yield 22.6%, overall yield 93.2%).

Compound 53 (570.9 g, 2.07 mol) was taken up in AcOH (3 L). Thismixture, with a total dissolved volume of 3.3 L, was divided into ten330 mL batches. Under a hydrogen atmosphere, to each batch was addedplatinum (IV) oxide (9.40 g, 0.041 mol) and each batch was thenhydrogenated at 500 psi for 16 hrs to 18 hrs. The batches were combinedand filtered through CELITE. The filter cake was washed with AcOH (500mL). The filtrate was concentrated under reduced pressure at 70° C. toprovide an oil. To the oil was added Et₂O (6 L). The mixture was stirredand cooled to 0° C. for 1 hr. The white precipitate that formed wasfiltered under reduced pressure and washed with Et₂O (2 L) to provide253.4 g of Compound 54,(1R,1′R,3r,3′R,5S,5′S)-9′-aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-amineacetate (yield 35.3%). The filtrate was evaporated under reducedpressure to provide a residue which was subjected to the same treatmentwith Et₂O. A second crop of 213.7 g of Compound 54 was isolated (yield32.1%). The filtrate was again evaporated under reduced pressure toprovide 201.1 g of Compound 54 (yield 25.4%, overall yield 92.8%).

The identity of Compound 54 was confirmed using ¹H-NMR.

Compound 54: ¹H-NMR: δ_(H) (ppm, 400 MHz, CD₃OD): 3.63 (3H, m), 3.42(1H, m), 2.36 (2H, m), 2.01 (5H, m), 1.89 (5H, m), 1.39-1.78 (13H, m),1.12 (2H, m).

In part 1, Compound 54 (439.0 g, 1.36 mol) and MeCN (4 L) wereintroduced into a reactor; the reactor temperature control was set to25° C. To this mixture were added TEA (412.9 g, 4.08 mol, 3 eq) and1-fluoro-2-nitrobenzene (194.2 g, 1.38 mol, 1 eq). The reaction mixturewas heated to reflux, refluxed for 6 days, then cooled to 0° C. Theyellow precipitate that formed was collected by filtration under reducedpressure. The filter cake was washed four times with DCM (2L for eachwash) and the filtrates were set aside. The remaining 91 g of solids,comprising recovered Compound 54, were dried and set aside.

In part 2, the reaction described in part 1 above was repeated using therecovered Compound 54 starting material except DMF (2 L) and K₂CO₃ (3eq) were used. After stirring for 2 hrs at 110° C., the reaction mixturewas cooled to a temperature of about 25° C. and poured into deionizedwater (4 L). This mixture was extracted six times with Et₂O (2L for eachextraction). The organic portions were combined and evaporated underreduced pressure to provide a residue.

The residue from part 2 and the filtrates from part 1 were combined andthe resulting combination was evaporated under reduced pressure toprovide an oil which was triturated with deionized water (4 L). Thesolids that formed were filtered under reduced pressure and washed withfurther deionized water. The solids were then dried under reducedpressure at 60° C. for 48 hrs to provide 402 g of Compound 55,(1R,1′R,3r,3′R,5S,5′S)—N-(2-nitrophenyl)-9′-aza[3,9′-bi(bicyclo[3.3.1]nonan)]-3′-amine,as a bright yellow solid (yield 77%).

Compound 55 (402 g, 1.05 mol) was taken up in MeOH (2.5 L). This mixturewas divided into ten batches. Under a hydrogen atmosphere, to each batchwas added 10% Pd/C (0.04 mol) and, with stirring, each batch washydrogenated at 50 psi for 3 hrs at a temperature of about 25° C. Thebatches were filtered through CELITE and the filter cake washed withMeOH. The filtrate was evaporated under reduced pressure to provide aresidue which was triturated with Et₂O then filtered under reducedpressure to provide Compound 56,N′-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)benzene-1,2-diamine,as a light brown solid (yield>99%).

5.6 Example 6 Synthesis of Compound 66

Using procedures similar to those described in Examples 4 and 5,Compound 66 was prepared from Compound 60.

The identity of Compound 61, (1R,6S)-bicyclo[4.3.1]decan-8-amine, wasconfirmed using MS.

Compound 61: MS: m/z=154.4 [M+H]⁺.

The identity of Compound 62,(1R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-one,was confirmed using ¹H-NMR and MS.

Compound 62: ¹H-NMR: δ_(H) (ppm, CD₃OD): 3.76 (br, 2H), 3.45 (m, 1H),3.13 (m, 1H), 2.70 (m, 2H), 2.38-2.20 (m, 4H), 1.99-1.76 (m, 9H),1.75-1.34 (m, 10H); MS: m/z=276.4 [M+H]⁺.

The identity of Compound 63,(1R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-oneoxime, was confirmed using ¹H-NMR and MS.

Compound 63: ¹H-NMR: δ_(H) (ppm, CDCl₃): 8.29 (br, 1H), 3.52 (br, 2H),3.03 (m, 2H), 2.63 (m, 1H), 2.27 (m, 4H), 1.95-1.26 (m, 20H); MS:m/z=291.4 [M+H]⁺.

The identity of Compound 64,(1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-amineacetate, was confirmed using ¹H-NMR and MS.

Compound 64: ¹H-NMR: δ_(H) (ppm, CD₃OD): 3.49 (m, 2H), 3.20 (m, 1H),3.05 (m, 1H), 2.27 (m, 4H), 2.04 (m, 1H), 1.91 (s, 3H), 1.81 (m, 7H),1.71-1.42 (m, 8H), 1.31-1.15 (m, 6H); MS: m/z=277.4 [M+H]⁺.

The identity of Compound 65,(1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-N-(2-nitrophenyl)-9-azabicyclo[3.3.1]nonan-3-amine,was confirmed using ¹H-NMR and MS.

Compound 65: ¹H-NMR: δ_(H) (ppm, CDCl₃): 8.17 (dd, J=1.7, 8.4 Hz, 1H),8.04 (d, J=7.3 Hz, 1H), 7.41 (m, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.60 (m,1H), 3.98 (m, 1H), 3.51 (m, 2H), 3.05 (m, 1H), 2.46 (m, 2H), 2.27 (m,2H), 2.02 (m, 1H), 1.86-1.52 (m, 12H), 1.49-1.32 (m, 4H), 1.25 (m, 2H),1.13 (m, 2H); MS: m/z=398.4 [M+H]⁺.

The identity of Compound 66 was confirmed using ¹H-NMR and MS.

Compound 66: ¹H-NMR: H (ppm, CDCl₃): 6.78 (m, 4H), 6.60 (m, 1H), 4.46(m, 1H), 3.91 (m, 3H), 3.74 (m, 1H), 3.11 (m, 2H), 2.79 (m, 2H), 2.55(m, 1H), 2.42 (m, 4H), 2.02-1.55 (m, 12H), 1.52-1.27 (m, 5H); MS:m/z=368.4 [M+H]⁺.

Compound 60, (1R,6S)-bicyclo[4.3.1]decan-8-one, was prepared byhydrogenating Compound 58 using palladium on carbon under a hydrogenatmosphere, for example, similarly to the preparation of Compound 50 inExample 5. Alternately, Compound 60 can be prepared by protecting theoxo group of Compound 59 followed by debromination with n-butyl lithium,quenching with water, and deprotection of the oxo group.

The identity of Compound 60 was confirmed using MS.

Compound 60: MS: m/z=153.4 [M+H]⁺.

Compound 58, (R)-bicyclo[4.3.1]dec-6-en-8-one, was prepared by methodsknown to the art, e.g., as described in House et al., J. Org. Chem.44(16):2819-2824 (1979) and House et al., J. Org. Chem. 45(10):1800-1806(1980). These House et al. references also describe the preparation ofCompound 59, (1S,6S)-1-bromobicyclo[4.3.1]decan-8-one.

The identity of Compound 58 was confirmed using MS.

Compound 58: MS: m/z=151.4 [M+H]⁺.

5.7 Example 7 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where is a Single Bond and Q_(x) is Present

Using procedures similar to those described above in Example 1, thefollowing Substituted Benzimidazole-Type Piperidine Compounds wereprepared from Compound 66. The co-reactant compounds are commerciallyavailable from, e.g., Sigma-Aldrich, or can be prepared by methods knownto the art.

H56b(i):2-((S)-2-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]midazol-2-yl)piperidin-1-yl)aceticacid.

H56b(i): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.71 (m, 2H), 7.31 (m, 2H), 6.58(br, s, 1H), 4.25 (m, 2H), 4.10 (br, s, 1H), 3.91 (m, 1H), 3.42 (m, 1H),2.99 (m, 2H), 2.66 (m, 3H), 2.47 (m, 5H), 2.23-1.91 (m, 11H), 1.85-1.76(m, 8H), 1.63-1.42 (m, 6H); MS: m/z=519.3 [M+H]⁺.

H6d:3-(3-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)propanoicacid.

H6d: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.8Hz, 1H), 7.36 (m, 2H), 5.69 (m, 1H), 4.55 (m, 2H), 4.37 (m, 2H), 4.01(m, 1H), 3.58 (m, 2H), 2.64 (m, 6H), 2.47 (m, 3H), 2.34 (m, 2H), 2.15(m, 2H), 2.04 (m, 3H), 1.79 (m, 8H), 1.56 (m, 4H); MS: m/z=505.2 [M+H]⁺.

H32d(ii):3-((S)-3-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)propanoicacid.

H32d(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.80 (d, J=7.8 Hz, 1H), 7.71 (d,J=7.8 Hz, 1H), 7.34 (m, 2H), 5.84 (m, 1H), 4.62 (m, 2H), 4.41 (m, 2H),4.01 (m, 2H), 3.88 (m, 1H), 3.82 (m, 1H), 3.83 (m, 3H), 2.89-2.53 (m,6H), 2.48-2.25 (m, 6H), 2.17 (m, 2H), 2.05 (br, s, 3H), 1.96-1.62 (m,8H), 1.55 (m, 4H); MS: m/z=519.3 [M+H]⁺.

H30d(ii):2-((S)-3-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)aceticacid.

H30d(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.70 (d, J=7.8 Hz, 1H), 7.62 (d,J=7.8 Hz, 1H), 7.24 (m, 2H), 5.33 (m, 1H), 4.26 (m, 4H), 4.13 (m, 1H),4.06 (m, 1H), 3.86 (m, 2H), 3.51 (m, 2H), 2.58 (m, 5H), 2.37 (m, 3H),2.20-1.70 (m, 15H), 1.48 (m, 5H); MS: m/z=505.2 [M+H]⁺.

H62d(ii):2-((S)-3-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetamide.

H62d(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.75 (d, J=8.0 Hz, 1H), 7.67 (d,J=8.0 Hz, 1H), 7.31 (m, 2H), 5.34 (m, 1H), 4.29 (m, 2H), 3.81 (m, 4H),3.40 (m, 1H), 2.76 (m, 1H), 2.59 (m, 3H), 2.36 (m, 3H), 2.09-1.56 (m,19H), 1.48 (m, 5H); MS: m/z=518.2 [M+H]⁺.

H4d:2-(3-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)aceticacid.

H4d: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.68 (m, 2H), 7.26 (m, 2H), 5.17 (br,s, 1H), 4.61 (m, 4H), 4.26 (br, 4H), 3.87 (br, s, 1H), 2.60 (m, 4H),2.37 (m, 3H), 2.06-1.61 (m, 14H), 1.47 (m, 5H); MS: m/z=491.2 [M+H]⁺.

H58d(ii):3-((S)-3-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)propanoicacid.

H58d(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.72 (d, J=8.0 Hz, 1H), 7.65 (d,J=8.0 Hz, 1H), 7.28 (m, 2H), 5.32 (br, s, 1H), 4.27 (br, s, 2H), 3.87(m, 3H), 3.39 (m, 4H), 2.88 (m, 2H), 2.69 (m, 1H), 2.56 (m, 3H), 2.36(m, 3H), 2.06 (m, 3H), 1.95 (m, 4H), 1.82-1.66 (m, 11H), 1.46 (m, 5H);MS: m/z=533.4 [M+H]⁺.

ZA07:2-(4-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)aceticacid.

ZA07: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.80 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.0Hz, 1H), 7.35 (m, 2H), 5.92 (m, 1H), 4.38 (m, 2H), 4.04 (m, 2H), 3.77(m, 4H), 3.52 (m, 2H), 2.75 (m, 2H), 2.61 (m, 2H), 2.48 (m, 3H), 2.39(m, 2H), 2.38-1.65 (m, 16H), 1.54 (m, 4H); MS: m/z=519.3 [M+H]⁺.

ZA08:3-(4-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)propanoicacid.

ZA08: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.80 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.34 (m, 2H), 5.92 (m, 1H), 4.38 (m, 2H), 4.08 (m, 2H), 3.71(m, 2H), 3.48 (m, 4H), 2.71 (m, 6H), 2.48 (m, 3H), 2.34 (m, 2H), 2.26(m, 5H), 2.03 (m, 3H), 1.83 (m, 8H), 1.56 (m, 4H); MS: m/z=533.4 [M+H]⁺.

ZA09:2-(4-((1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-1-yl)aceticacid.

ZA09: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.82 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.38 (m, 2H), 5.40 (m, 1H), 4.27 (m, 2H), 3.95 (m, 3H), 3.57(m, 2H), 3.01 (m, 4H), 2.65 (m, 4H), 2.36 (m, 3H), 2.21 (m, 1H), 2.08(m, 2H), 1.96 (m, 5H), 1.70 (m, 11H), 1.47 (m, 5H); MS: m/z=533.4[M+H]⁺.

ZA10:3-(4-((1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-1-yl)propanoicacid.

ZA10: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.68 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8Hz, 1H), 7.22 (m, 2H), 5.67 (m, 1H), 4.28 (m, 2H), 3.90 (m, 1H), 3.47(m, 2H), 3.25 (m, 2H), 3.12-2.95 (m, 4H), 2.78 (m, 2H), 2.58 (m, 6H),2.37 (m, 3H), 2.28-1.53 (m, 17H), 1.45 (m, 4H); MS: m/z=547.3 [M+H]⁺.

H56b(ii):2-((R)-2-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)aceticacid.

H56b(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.77 (d, J=8.0 Hz, 1H), 7.68 (d,J=8.0 Hz, 1H), 7.33 (m, 2H), 6.55 (br, s, 1H), 4.34 (br, s, 1H), 4.24(m, 1H), 4.10 (br, s, 1H), 3.91 (m, 1H), 3.35 (m, 1H), 3.01 (m, 2H),2.67 (m, 2H), 2.47 (m, 5H), 2.20-1.86 (m, 11H), 1.77 (m, 7H), 1.60 (m,6H); MS: m/z=519.3 [M+H]⁺.

H30b(ii):2-((R)-2-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)aceticacid.

H30b(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.66 (d, J=8.0 Hz, 1H), 7.56 (d,J=8.0 Hz, 1H), 7.22 (m, 2H), 6.34 (br, s, 1H), 4.33 (m, 1H), 4.12 (m,2H), 3.73 (m, 1H), 3.26 (m, 1H), 3.02 (m, 2H), 2.53 (m, 4H), 2.28 (m,6H), 1.95 (m, 10H), 1.66 (m, 7H), 1.45 (m, 4H); MS: m/z=505.4 [M+H]⁺.

H32b(ii):3-((R)-2-(1-((1R,3R,5S)-9-((1R,6S,8s)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)propanoicacid.

H32b(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.80-7.73 (m, 1H), 7.70-7.61 (m,1H), 7.36-7.19 (m, 2H), 5.84-5.70 (m, 1H), 4.34-4.26 (m, 1H), 4.24-4.16(m, 1H), 4.14-4.05 (m, 1H), 3.76-3.64 (m, 1H), 3.10-3.00 (m, 1H),2.95-2.83 (m, 1H), 2.77-2.65 (m, 2H), 2.58-2.34 (m, 10H), 2.32-2.20 (m,1H), 2.16-1.67 (m, 14H), 1.67-1.45 (m, 7H); MS: m/z=519.3 [M+H]⁺.

5.8 Example 8 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where is a Single Bond and Q_(x) is Present

Using procedures similar to those described above in Example 1, thefollowing Substituted Benzimidazole-Type Piperidine Compounds wereprepared from Compound 56 and the appropriate co-reactants. Theco-reactant compounds are commercially available from, e.g.,Sigma-Aldrich, or can be prepared by methods known to the art.

B56c(i):2-((R)-3-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)aceticacid.

B56c(i): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.98 (d, J=7.6 Hz, 1H), 7.81 (d,J=7.6 Hz, 1H), 7.56 (m, 2H), 6.08 (br, s, 1H), 4.42-4.30 (m, 5H), 3.90(m, 1H), 3.71 (m, 2H), 2.78 (m, 4H), 2.43 (m, 3H), 2.28 (m, 9H), 2.05(m, 2H), 1.85 (m, 8H), 1.77 (m, 2H); MS: m/z=505.6 [M+H]⁺.

B56c(ii):2-((S)-3-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)aceticacid.

B56c(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.79 (d, J=7.8 Hz, 1H), 7.70 (d,J=7.8 Hz, 1H), 7.34 (m, 2H), 5.71 (br, s, 1H), 4.23 (m, 2H), 3.99 (br,s, 1H), 3.65 (m, 3H), 3.45 (br, s, 1H), 3.01 (m, 2H), 2.65 (m, 4H), 2.39(m, 1H), 2.19-1.98 (m, 13H), 1.72-1.53 (m, 10H); MS: m/z=505.6 [M+H]⁺.

ZA11:(1R,1′R,3r,3′R,5S,5′S)-3′-(2-((R)-1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-3-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).

ZA11: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.78 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.7Hz, 1H), 7.28 (m, 2H), 5.06 (m, 1H), 3.71-3.56 (m, 11H), 3.40 (m, 4H),3.09 (m, 1H), 2.73 (br s, 2H), 2.48-2.18 (m, 7H), 2.13-1.92 (m, 7H),1.90-1.57 (m, 14H), 1.21 (m, 2H); MS: m/z=593.3 [M+H]⁺.

ZA12:(1R,1′R,3r,3′R,5S,5′S)-3′-(2-((S)-1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-3-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).

ZA12: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.79 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.8Hz, 1H), 7.30 (m, 2H), 5.25 (m, 1H), 3.96-3.76 (m, 5H), 3.65 (m, 4H),3.54 (m, 2H), 3.42 (m, 2H), 3.32 (m, 3H), 3.03 (br s, 3H), 2.62-2.32 (m,5H), 2.12 (m, 7H), 2.02-1.86 (m, 7H), 1.82-1.63 (m, 10H), 1.43 (m, 2H);MS: m/z=593.3 [M+H]⁺.

5.9 Example 9 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where is a Single Bond and Q_(x) is Present

Under an argon atmosphere, in a dry flask containing a solution ofCompound 44 (3.92 g, 10.68 mmol), prepared in Example 5, in THF (20 mL)at −10° C. was added portionwise a solution of CDI (2.42 g, 14.95 mmol,Sigma-Aldrich) in THF (37 mL). The resulting reaction mixture wasstirred for 1 hr while it gradually warmed to 5° C. Thereafter, themixture was cooled to 0° C. and water was added. The mixture wasextracted with EtOAc, washed with brine, and concentrated to provide 3.7g of a residue. The residue was chromatographed on a silica gel columneluted with a gradient of from 100:0 hexanes:EtOAc to 90:10hexanes:EtOAc followed by elution with 10:90 MeOH:chloroform to provide3.35 g of Compound 68,1-((1R,1′R,3r,3′R,5S,5′S,7S)-7-methyl-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2(3H)-one(yield 79.8%).

The identity of Compound 68 was confirmed using LC/MS.

Compound 68: LC/MS: m/z=394 [M+H]⁺ (Calc.: 395).

In a 30 mL pressure tube containing a suspension of Compound 68 (0.50 g,1.27 mmol) in DCE (3.8 mL) at a temperature of about 25° C. was added inone portion POBr₃ (1.82 g, 6.36 mmol, Sigma-Aldrich). The tube wassealed and the resulting reaction mixture kept for 22 hrs in an oil bathset at 100° C. The mixture was then poured onto an ice and water slurry,extracted with DCM, neutralized with 10% aqueous Na₂CO₃, washed withbrine, and concentrated to provide 0.61 g of Compound 69,(1R,1′R,3r,3′R,5S,5′S,7S)-3′-(2-bromo-1H-benzo[d]imidazol-1-yl)-7-methyl-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),as a solid which was used directly in the next step.

The identity of Compound 69 was confirmed using LC/MS.

Compound 69: LC/MS: m/z=456 [M+H]⁺ (Calc.: 455).

Into a 10 mL pressure tube containing Compound 69 (0.30 g, 0.66 mmol)was added (S)-tert-butyl pyrrolidine-2-carboxylate (Compound 70, 1.5 mL,5.84 mmol, Sigma-Aldrich). The tube was sealed and the resultingreaction mixture was kept for 9 hrs in an oil bath set at 125° C.Thereafter, the resulting brownish residue was dissolved in DCM andchromatographed on a silica gel column eluted with a gradient of from0:100 EtOAc:hexanes to 20:80 EtOAc:hexanes to provide 81 mg ofSubstituted Benzimidazole-Type Piperidine Compound ZA13, (S)-tert-butyl1-(1-((1R,1′R,3r,3′R,5S,5′S,7R)-7-methyl-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-2-carboxylate,as an amber semi-solid (yield 22.5%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA13was confirmed using LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA13: LC/MS: m/z=547[M+H]⁺ (Calc.: 546).

To a solution of Compound ZA13 (80 mg, 0.146 mmol) in DCM (0.8 mL) at atemperature of about 25° C. was added TFA (0.17 mL, 2.19 mmol). Theresulting reaction mixture was kept at a temperature of about 25° C. for16 hrs then evaporated to dryness. The residue was triturated with Et₂Oto provide a solid which was chromatographed by preparative HPLC toprovide 35 mg of the TFA salt of Substituted Benzimidazole-TypePiperidine Compound ZA14. This salt was neutralized with 10% aqueousNa₂CO₃ and extracted with DCM to provide 20 mg of SubstitutedBenzimidazole-Type Piperidine Compound ZA14,(S)-1-(1-((1R,1′R,3r,3′R,5S,5′S,7R)-7-methyl-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-2-carboxylicacid (yield 27.9%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA14was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA14: ¹H-NMR: δ_(H)(ppm, 300 MHz, CD₃OD): 7.70-7.64 (m, 1H), 7.54-7.49 (m, 1H), 7.47-7.41(m, 2H), 5.45-5.32 (m, 1H), 4.96 (t, J=7.0 Hz, 1H), 4.32 (d, J=7.8 Hz,1H), 4.27-4.20 (m, 1H), 4.04-3.97 (q, J=6.4 Hz, 1H), 3.93-3.83 (m, 1H),3.71-3.64 (t, J=10.3 Hz, 1H), 2.87-2.77 (m, 1H), 2.74-2.56 (m, 4H),2.45-2.29 (m, 3H), 2.28-2.20 (m, 2H), 2.19-2.06 (m, 6H), 2.02-1.88 (m,2H), 1.88-1.66 (m, 6H), 1.14-1.08 (d, J=12.5 Hz, 1H), 0.92 (d, J=6.4 Hz,3H), 0.75-0.64 (t, J=12.3 Hz, 2H); LC/MS: m/z=491 [M+H]⁺ (Calc.: 490).

Compound 72,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-bromo-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),was prepared in a similar manner to the previously-described preparationof Compound 69 except that Compound 56 was used in place of Compound 44.

The identity of Compound 71,1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2(3H)-one,was confirmed using LC/MS.

Compound 71: LC/MS: m/z=380 [M+H]⁺ (Calc.: 379).

The identity of Compound 72 was confirmed using LC/MS.

Compound 72: LC/MS: m/z=442 [M+H](Calc.: 441).

Thereafter, Substituted Benzimidazole-Type Piperidine Compound ZA15,(S)-tert-butyl1-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-2-carboxylate(yield 11.1%), was prepared from Compounds 72 and 70 in a similar mannerto the previously-described preparation of Compound ZA13.

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA15was confirmed using LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA15: LC/MS: m/z=533[M+H]⁺ (Calc.: 532).

Substituted Benzimidazole-Type Piperidine Compound ZA16,(S)-1-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-2-carboxylicacid (yield 48.3%), was prepared in a similar manner to thepreviously-described preparation of Compound ZA14.

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA16was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA16: ¹H-NMR: δ_(H)(ppm, 300 MHz, CD₃OD): 7.62-7.68 (m, 1H), 7.55-7.48 (m, 1H), 7.46-7.39(m, 2H), 5.43-5.30 (m, 1H), 4.93 (t, J=7.5 Hz, 1H), 4.36-4.27 (m, 2H),4.27-4.20 (m, 1H), 4.03-3.95 (q, J=9.0 Hz, 1H), 3.70-3.62 (m, 1H),2.86-2.75 (m, 1H), 2.73-2.56 (m, 4H), 2.40-2.29 (m, 2H), 2.28-2.02 (m,9H), 2.02-1.92 (m, 2H), 1.88-1.70 (m, 7H), 1.68-1.58 (m, 2H), 1.54-1.41(m, 1H); LC/MS: m/z=477 [M+H]⁺ (Calc.: 476).

Compound 72 (0.73 g, 1.65 mmol) and tert-butyl 2-(piperazin-1-yl)acetate(Compound 7, 1.18 g, 5.90 mmol, Sigma-Aldrich) were combined in apressure tube and the resulting reaction mixture was kept for 9 hrs onan oil bath set at 125° C. The mixture was then cooled to a temperatureof about 25° C. and the resulting residue was chromatographed on asilica gel column eluted with a gradient of from 10:90 EtOAc:hexanes to30:70 EtOAc:hexanes to provide 0.20 g of Substituted Benzimidazole-TypePiperidine Compound ZA17, tert-butyl2-(4-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)acetate.

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA17was confirmed using LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA17: LC/MS: m/z=562[M+H]⁺ (Calc.: 561).

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA17(0.198 g, 0.35 mmol) in DCM (1.9 mL) at a temperature of about 25° C.was added TFA (0.41 mL, 5.28 mmol). The resulting reaction mixture waskept at a temperature of about 25° C. for 16 hrs then evaporated todryness. The residue was chromatographed by preparative HPLC,neutralized with 10% aqueous Na₂CO₃, and extracted with DCM to provide55 mg of Substituted Benzimidazole-Type Piperidine Compound ZA18,2-(4-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)piperazin-1-yl)aceticacid (yield 31%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA18was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA18: ¹H-NMR: δ_(H)(ppm, 300 MHz, CD₃OD): 7.65-7.60 (m, 2H), 7.37-7.29 (m, 2H), 5.48-5.36(m, 1H), 4.37-4.29 (m, 1H), 4.28-4.21 (m, 2H), 3.92 (s, 2H), 3.57-3.47(m, 8H), 2.70-2.62 (m, 4H), 2.50-2.35 (m, 1H), 2.27-1.96 (m, 9H),1.85-1.71 (m, 7H), 1.69-1.56 (q, J=9.9 Hz, 2H), 1.54-1.42 (m, 1H);LC/MS: m/z=506 [M+H]⁺ (Calc.: 505).

Substituted Benzimidazole-Type Piperidine Compound ZA19, (R)-tert-butyl1-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-2-carboxylate(yield 18.8%), was prepared in a similar manner to thepreviously-described preparation of Substituted Benzimidazole-TypePiperidine Compound ZA13 except that a molar excess of (R)-tert-butylpyrrolidine-2-carboxylate (Compound 74, Sigma-Aldrich) was used in placeof Compound 70.

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA19was confirmed using LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA19: LC/MS: m/z=562[M+H]⁺ (Calc.: 561).

Thereafter, Substituted Benzimidazole-Type Piperidine Compound ZA20,(R)-1-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-2-carboxylicacid, was prepared in a similar manner to the previously-describedpreparation of Substituted Benzimidazole-Type Piperidine Compound ZA14(yield 16%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA20was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA20: ¹H-NMR: δ_(H)(ppm, 300 MHz, CD₃OD): 7.72-7.66 (m, 1H), 7.55-7.49 (m, 1H), 7.48-7.41(m, 2H), 5.43-5.31 (m, 1H), 4.96 (t, J=7.5 Hz, 1H), 4.36-4.27 (m, 2H),4.27-4.20 (m, 1H), 4.06-3.97 (q, J=9.0 Hz, 1H), 3.73-3.66 (t, J=9.0 Hz,1H), 2.88-2.77 (m, 1H), 2.75-2.55 (m, 4H), 2.42-2.28 (m, 2H), 2.28-2.03(m, 9H), 2.02-1.92 (m, 2H), 1.88-1.70 (m, 7H), 1.68-1.58 (m, 2H),1.55-1.41 (m, 1H); LC/MS: m/z=506 [M+H]⁺ (Calc.: 505).

5.10 Example 10 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where is a Single Bond Q_(x) is Present

Using procedures similar to those described above in Example 1, thefollowing Substituted Benzimidazole-Type Piperidine Compounds wereprepared from the appropriate diamine, e.g., 1′-benzene-1,2-diamine,3′-pyridine-2,3-diamine, 4′-pyridine-3,4-diamine, or3′-pyridine-3,4-diamine, and the appropriate co-reactants. Said diaminesare commercially available or can be prepared by methods known to theart, e.g., as described in U.S. Pat. App. Pub. Nos. US 2010/0216726 A1(see, e.g., Examples 3, 14, 30, 32, 35, 38, 40, and 42-44), US2011/0178090 A1 (see, e.g., Examples 1, 2, 4, 5, and 9), and/orInternational PCT Publication No. WO 2012/085648 A1 (see, e.g., Examples12 and 13), which are hereby incorporated by reference in theirentireties. The co-reactant compounds are commercially available from,e.g., Sigma-Aldrich, or can be prepared by methods known to the art.

E32c(ii):3-((R)-2-(1-((1R,3r,5S)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)propanoicacid.

E32c(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.82-7.74 (m, 1H), 7.69-7.61 (m,1H), 7.36-7.22 (m, 2H), 5.75-5.59 (m, 1H), 4.24-4.11 (m, 1H), 4.06-3.86(m, 2H), 3.53-3.40 (m, 1H), 3.21-3.11 (m, 1H), 3.11-2.96 (m, 1H),2.73-2.18 (m, 10H), 2.15-1.70 (m, 11H), 1.69-1.42 (m, 13H), 1.37-1.23(m, 1H), 0.94-0.83 (m, 1H); MS: m/z=521.4 [M+H]⁺.

E30c(ii):2-((R)-2-(1-((1R,3r,5S)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)aceticacid.

E30c(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81-7.69 (m, 1H), 7.65-7.53 (m,1H), 7.36-7.17 (m, 2H), 6.18-5.71 (m, 1H), 4.40-4.20 (m, 1H), 4.09-3.86(m, 2H), 3.72-3.51 (m, 1H), 3.45-3.33 (m, 1H), 3.11-2.97 (m, 1H),2.66-2.27 (m, 6H), 2.27-1.74 (m, 12H), 1.73-1.45 (m, 16H); MS: m/z=507.3[M+H]⁺.

E56c(ii):2-((R)-2-(1-((1R,3r,5S)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)aceticacid.

E56c(ii): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.80-7.71 (m, 1H), 7.69-7.59 (m,1H), 7.38-7.20 (m, 2H), 6.51-6.30 (m, 1H), 4.26-3.95 (m, 3H), 3.92-3.74(m, 1H), 3.27-3.02 (m, 2H), 2.98-2.82 (m, 1H), 2.73-2.52 (m, 3H),2.52-2.28 (m, 3H), 2.26-1.80 (m, 12H), 1.80-1.46 (m, 17H); MS: m/z=521.4[M+H]⁺.

5.11 Example 11 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where is —CH₂— and Q_(x) is Present

To a round-bottomed flask was added Compound 56 (353 mg, 1.0 mmol),prepared in Example 6, 2-chloroacetic acid (Compound 75, 113 mg, 1.2mmol, Sigma-Aldrich), and 6 mol/L HCl (5 mL). The resulting reactionmixture was heated to 90° C. and stirred at that temperature for 16 hrs.Thereafter, the mixture was cooled to a temperature of about 25° C.,neutralized with 2 mol/L NaOH to a pH of about pH7. The precipitate thatformed was filtered, washed with water, and dried to provide 206 mg ofSubstituted Benzimidazole-Type Piperidine Compound ZA21,(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(chloromethyl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane),as a brown solid (yield 50%) which was used directly in the next step.

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA21(412 mg, 1.0 mmol) in DMF (4 mL) was added methylpiperidine-4-carboxylate (Compound 76, 143 mg, 1.0 mmol, Sigma-Aldrich)and TEA (0.5 mL). The resulting reaction mixture was heated to 40° C.and stirred at that temperature for 12 hrs. Thereafter, the mixture wascooled to a temperature of about 25° C., diluted with EtOAc (200 mL),washed with brine, dried (over Na₂SO₄), and evaporated to dryness. Theresidue was chromatographed on a COMBIFLASH apparatus eluted with agradient of from 0:100 MeOH:DCM to 5:95 MeOH:DCM to provide 100 mg ofSubstituted Benzimidazole-Type Piperidine Compound ZA22, methyl1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylate,as a brown solid (yield 20%) which was used directly in the next step.

To a round-bottomed flask was added Substituted Benzimidazole-TypePiperidine Compound ZA22 (100 mg, 0.19 mmol) and 2 mol/L aqueous KOH (2mL). The resulting mixture was heated to 40° C. and stirred at thattemperature for 3 days. Thereafter, the mixture was cooled to atemperature of about 25° C. then 1 mol/L HCl was added to achieve a pHof about pH5. After twice extracting with 20:1 DCM:MeOH (50 mL for eachextraction), the organic portions were combined, dried, and evaporatedto dryness to provide 70 mg of Substituted Benzimidazole-Type PiperidineCompound ZA23,1-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidine-4-carboxylicacid, as a pale-yellow solid (yield 72%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA23was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA23: ¹H-NMR: δ_(H)(ppm, 400 MHz, MeOH-d₄): 7.87 (1H, d, J=8.5 Hz), 7.76 (1H, d, J=8.1 Hz),7.44 (1H, t, J=7.5 Hz), 7.36 (1H, t, J=7.7 Hz), 5.89 (1H, m), 4.76 (2H,m), 4.40 (1H, m), 4.30 (2H, m), 3.60 (2H, m), 3.20 (1H, m), 2.69 (5H,m), 2.39 (3H, m), 2.21 (8H, m), 2.01 (4H, m), 1.87-1.58 (10H, m); LC/MS:m/z=505.4 [M+H]⁺ (Calc.: 504.7).

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA21(412 mg, 1.0 mmol) in DMF (4 mL) was added Compound 73 (198 mg, 1.5mmol) and TEA (0.5 mL). The resulting reaction mixture kept at atemperature of about 25° C. for 12 hrs and then diluted with EtOAc (200mL), washed with brine, dried (over Na₂SO₄), and evaporated to dryness.The residue was chromatographed on a COMBIFLASH apparatus eluted with agradient of from 0:100 DCM:MeOH to 5:95 DCM:MeOH to provide 113 mg ofSubstituted Benzimidazole-Type Piperidine Compound ZA24, tert-butyl2-(4-((1-((1R1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)acetate,as a solid (yield 20%) which was used directly in the next step.

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA24(100 mg, 0.17 mmol) in DCM (4 mL) was added TFA (2 mL). The resultingreaction mixture was stirred at a temperature of about 25° C. for 10 hrsthen 1 mol/L NaOH was added to achieve a pH of about pH4. After twiceextracting with 20:1 DCM:MeOH (50 mL for each extraction), the organicportions were combined, dried, and evaporated to dryness. The residuewas chromatographed on a COMBIFLASH apparatus eluted with a gradient offrom 0:100 MeOH:DCM to 5:95 MeOH:DCM to provide 30 mg of SubstitutedBenzimidazole-Type Piperidine Compound ZA25,2-(4-((1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)aceticacid, as a white foam (yield 33%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA25was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA25: ¹H-NMR: δ_(H)(ppm, 400 MHz, MeOH-d₄): 7.79 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=8.1 Hz),7.35 (2H, m), 5.34 (1H, m), 4.35-4.15 (3H, m), 3.94 (4H, m), 3.33 (4H,m), 2.78 (2H, m), 2.62 (6H, m), 2.32 (1H, m), 2.11 (6H, m), 1.99-1.79(3H, m), 1.75-1.47 (10H, m); LC/MS: m/z=520.3 [M+H]⁺ (Calc.: 519.7).

5.12 Example 12 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where is ═N— and Q_(x) is Absent

Compound 78,N-(1-(1-cyclooctylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)cyanamide,was prepared from readily available materials according to knownmethods, such as those disclosed in EP 0029707 B1, e.g., ReferenceExamples 19 and 20, and U.S. Pat. No. 6,867,222 B2, e.g., Examples 13and 14, which are hereby incorporated by reference in their entireties.

To a mixture of Compound 78 (200 mg, 26 mmol) and EtOH (10 mL) at atemperature of about 25° C. was added 20% sodium ethoxide in EtOH (0.2mL). After stirring at a temperature of about 25° C. for 30 min, thereaction mixture was warmed to a temperature of 70° C. and stirred for 3hrs. After cooling to a temperature of about 25° C., the reactionmixture was diluted with EtOAc (40 mL) and water (4 mL). The organicportion was separated, concentrated under reduced pressure, andchromatographed with a silica gel column eluted with 1:10 MeOH:DCM toprovide 100 mg of Substituted Benzimidazole-Type Piperidine CompoundZA26 as a white solid (yield 45%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA26,ethyl1-(1-cyclooctylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-ylidenecarbamimidate,was confirmed using ¹H NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA26: ¹H NMR: δ_(H)(400 MHz, CDCl₃): 9.4 (br, 1H), 7.48-7.53 (m, 2H), 7.04-7.12 (m, 2H),5.3 (br, 1H), 4.62-4.71 (m, 1H), 4.37 (q, 2H, 7.2 Hz), 2.94-2.98 (m,2H), 2.66-2.71 (m, 1H), 2.48-2.55 (m, 2H), 2.34-2.42 (m, 2H), 1.74-1.84(m, 6H), 1.46-1.64 (m, 10H), 1.37 (t, 3H, 7.1 Hz); LC/MS (100%,t_(r)=4.902 min): m/z=398.5 [M+H]⁺ (Calc.: 397.5).

To a mixture of Compound 78 (200 mg, 26 mmol) in THF (10 mL) at atemperature of about 25° C. was added 2 mol/L aqueous HCl (2 mL). Afterstirring at a temperature of about 25° C. for 30 min, the reactionmixture was warmed to a temperature of 70° C. and stirred for 3 hrs.After cooling to a temperature of about 25° C., the reaction mixture wasdiluted with EtOAc (40 mL) and neutralized with 2 mol/L aqueous NaOH.The organic portion was separated, concentrated under reduced pressure,and chromatographed with a silica gel column eluted with 1:10 MeOH:DCMto provide 120 mg of Substituted Benzimidazole-Type Piperidine CompoundZA27 as a white solid (yield 55%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA27,1-(1-(1-cyclooctylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)urea,was confirmed using ¹H NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA27: ¹H NMR: δ_(H)(400 MHz, CDCl₃): 11.8 (s, 1H, —NH), 7.48 (br, 1H), 7.08-7.22 (m, 3H),4.96 (br, 2H, —NH₂), 2.92-2.98 (m, 2H), 2.64-2.68 (m, 1H), 2.40-2.52 (m,4H), 1.40-1.82 (m, 16H); LC/MS (100%, t_(r)=4.612 min): m/z=370.5 [M+H]⁺(Calc.: 369.5).

In a manner similar to the preparation of Substituted Benzimidazole-TypePiperidine Compound ZA26, 120 mg of Substituted Benzimidazole-TypePiperidine Compound ZA28 was prepared as a white solid (yield 54%)except that O-methylhydroxylamine hydrochloride (Sigma-Aldrich) was usedin place of sodium ethoxide.

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA28,1-(1-(1-cyclooctylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-ylidene)-3-methoxyguanidine,was confirmed using ¹H NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA28: ¹H NMR: δ_(H)(400 MHz, CDCl₃): 7.04-7.60 (m, 4H), 4.42-4.61 (m, 2H), 3.82 (s, 3H),3.76 (s, 1H), 3.68 (s, 1H), 2.92-2.96 (m, 2H), 2.64-2.71 (m, 1H),2.38-2.52 (m, 4H), 1.44-1.84 (m, 16H); LC/MS (100%, t_(r)=4.716 min):m/z=399.6 [M+H]⁺ (Calc.: 398.6).

Compound 79,2-(2-(cyanoimino)-3-(1-cyclooctylpiperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide,was prepared from readily available materials according to knownmethods, such as those disclosed in EP 0029707 B1, e.g., ReferenceExamples 19 and 20, and U.S. Pat. No. 6,867,222 B2, e.g., Examples 13and 14, which are hereby incorporated by reference in their entireties.

In a manner similar to the preparation of Substituted Benzimidazole-TypePiperidine Compound ZA26, 180 mg of Substituted Benzimidazole-TypePiperidine Compound ZA29 was prepared as a white solid (yield 70%) byusing MeOH in place of EtOH and 4 mol/L HCl in 1,4-dioxane in place of 2mol/L aqueous HCl.

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA29,(E)-methyl1-(2-amino-2-oxoethyl)-3-(1-cyclooctylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-ylidenecarbamate,was confirmed using ¹H NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA29: ¹H NMR: δ_(H)(400 MHz, CDCl₃): 7.6 (br, 1H), 7.16-7.22 (m, 2H), 7.04-7.07 (m, 1H),4.84 (s, 2H), 4.76 (br, 2H, —NH₂), 4.56 (br, 1H), 3.8 (s, 3H, —OCH₃),2.92-2.98 (m, 2H), 2.64-2.68 (m, 1H), 2.40-2.92 (m, 5H), 1.40-1.92 (m,18H); LC/MS (100%, t_(r)=4.518 min): m/z=442.5 [M+H]⁺ (Calc.: 441.5).

5.13 Example 13 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where is —NH— and Q_(x) is Absent

To a solution of Compound 56 (200 mg, 0.566 mmol) in DCM (2.0 mL) in icebath was added with stirring ethyl 2-isocyanatoacetate (88 mg, 0.679mmol, Sigma Aldrich). The resulting reaction mixture was allowed to warmto a temperature of about 25° C. and then stirred for 1.5 hrs at thattemperature. Thereafter, evaporation to dryness and drying under reducedpressure provided 280 mg of Compound 80, ethyl2-(3-(2-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-ylamino)phenyl)ureido)acetate,which was used directly in the next step.

To Compound 80, taken directly from the previous step, was added POCl₃(2.0 mL, Sigma Aldrich). The resulting reaction mixture was heated to100° C. and stirred at that temperature for 2 hrs. Thereafter, themixture was cooled to a temperature of about 25° C., diluted withchloroform, and neutralized with a saturated NaHCO₃ aqueous solution.The aqueous portion was separated and extracted twice with chloroform.The organic portions were combined, dried (over MgSO₄), filtered, andconcentrated to dryness. The residue was chromatographed on a silica gelcolumn eluted with n-hexane and EtOAc to provide 223 mg of SubstitutedBenzimidazole-Type Piperidine Compound ZA30, ethyl2-((1-((1R,1′R,3r,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)amino)acetate(yield 85% for two steps).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA30was confirmed using ¹H-NMR.

Substituted Benzimidazole-Type Piperidine Compound ZA30: ¹H-NMR: δ_(H)(ppm, 400 MHz, CDCl₃): 1.08-2.30 (m, 27H), 3.48-3.63 (m, 3H), 4.28 (m,2H), 4.40 (s, 2H), 4.61 (m, 1H), 4.92 (brs, 1H), 7.01-7.15 (m, 2H), 7.41(m, 1H), 7.52 (m, 1H).

To a suspension of Substituted Benzimidazole-Type Piperidine CompoundZA30 (220 mg, 0.473 mmol) in THF (1.5 mL) and EtOH (1.5 mL) was added a2 mol/L NaOH solution (0.71 mL, 1.42 mmol). The resulting reactionmixture was stirred at a temperature of about 25° C. for 2 hrs.Thereafter, 2 mol/L aqueous HCl (0.71 mL, 1.42 mmol) was added. Theresulting precipitate was collected by filtration and dried underreduced pressure to provide 173 mg of Substituted Benzimidazole-TypePiperidine Compound ZA31,2-((1-((1R,1′R,3r,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)amino)aceticacid (yield 84%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA31was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA31: ¹H-NMR: δ_(H)(ppm, 400 MHz, CD₃OD): 1.59-2.68 (m, 24H), 4.14 (s, 2H), 4.26-4.33 (m,3H), 5.69 (m, 1H), 7.30 (m, 2H), 7.67 (m, 1H), 8.11 (m, 1H); LC/MS:m/z=437.3 [M+H]⁺ (Calc.: 436).

Compound 82, ethyl2-(3-(2-(((1R,3r,5S)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)amino)phenyl)ureido)acetate(265 mg), was prepared from Compound 81,N¹-((1R,3r,5S)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)benzene-1,2-diamine(200 mg) by a procedure similar to that for preparing Compound 80 fromCompound 56. Compound 81 is commercially available or can be prepared bymethods known to the art, e.g., as described in U.S. Pat. App. Pub. Nos.US 2010/0216726 A1 (see, e.g., Examples 3, 14, 30, 32, 35, 38, 40, and42-44), US 2011/0178090 A1 (see, e.g., Examples 1, 2, 4, 5, and 9),and/or International PCT Publication No. WO 2012/085648 A1 (see, e.g.,Examples 12 and 13), which are hereby incorporated by reference in theirentireties.

Substituted Benzimidazole-Type Piperidine Compound ZA32, ethyl2-((1-((1R,5S)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)amino)acetate(171 mg, yield 66%), was prepared from Compound 82 (265 mg) by aprocedure similar to that for preparing Substituted Benzimidazole-TypePiperidine Compound ZA30 from Compound 80.

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA32was confirmed using ¹H-NMR.

Substituted Benzimidazole-Type Piperidine Compound ZA32: ¹H-NMR: δ_(H)(ppm, 400 MHz, CDCl₃): 1.16-2.30 (m, 31H), 3.07 (brs, 1H), 3.56 (brs,2H), 4.29 (m, 2H), 4.39 (s, 2H), 4.57 (m, 1H), 4.88 (s, 1H), 7.00-7.19(m, 2H), 7.34 (m, 1H), 7.48 (m, 1H).

Substituted Benzimidazole-Type Piperidine Compound ZA33,2-((1-((1R,5S)-9-cyclodecyl-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)amino)aceticacid (120 mg, yield 75%), was prepared from SubstitutedBenzimidazole-Type Piperidine Compound ZA32 (170 mg) by a proceduresimilar to that for preparing Substituted Benzimidazole-Type PiperidineCompound ZA31 from Compound ZA30.

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA33was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA33: ¹H-NMR: δ_(H)(ppm, 400 MHz, CD₃OD): 1.56-2.49 (m, 28H), 3.69 (brs, 1H), 4.05 (m, 4H),5.22 (m, 1H), 7.04-7.11 (m, 2H), 7.33 (m, 1H), 7.44 (m, 1H); LC/MS:m/z=453.3 [M+H]⁺ (Calc.: 452).

5.14 Example 14 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where is —CH₂— or —CH═N— and Q_(x) is Absent

To a solution of Compound 56 (300 mg, 0.849 mmol) in DCM (3.0 mL) in icebath was added with stirring 2-chloro-2-oxoethyl acetate (122 mg, 0.891mmol, Sigma Aldrich). The resulting reaction mixture was stirred in icebath for 30 min then diluted with chloroform and a saturated NaHCO₃aqueous solution. The aqueous portion was extracted with chloroform. Theorganic portions were combined, dried (over MgSO₄), filtered, andconcentrated to dryness to provide 435 mg of Compound 83,2-((2-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-ylamino)phenyl)amino)-2-oxoethylacetate (yield>99.5%), which was used directly in the next step.

To a solution of Compound 83 (435 mg) in toluene (2.0 mL) and1,4-dioxane (2.0 mL) was added AcOH (0.097 mL, 1.70 mmol). The resultingreaction mixture was heated to 100° C., and stirred at that temperaturefor 13 hrs. Thereafter, the mixture was cooled to a temperature of about25° C. and poured into chloroform and a saturated NaHCO₃ aqueoussolution. The aqueous portion was extracted with chloroform. The organicportions were combined, dried (over MgSO₄), filtered, and concentratedto dryness. The residue was chromatographed on a silica gel columneluted with n-hexane and EtOAc containing 5% TEA to provide 220 mg ofSubstituted Benzimidazole-Type Piperidine Compound ZA34,(1-((1R,1′R,3r,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methylacetate (yield 59% for two steps).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA34was confirmed using ¹H-NMR.

Substituted Benzimidazole-Type Piperidine Compound ZA34: ¹H-NMR: δ_(H)(ppm, 400 MHz, CDCl₃): 1.09-2.33 (m, 27H), 3.41-3.61 (m, 3H), 4.86 (1H,m), 5.40 (s, 2H), 7.27 (m, 2H), 7.68-7.82 (m, 2H).

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA34(220 mg, 0.505 mmol) in MeOH (4.0 mL) was added 2 mol/L aqueous NaOH(0.758 mL, 1.515 mmol). The resulting reaction mixture was stirred at atemperature of about 25° C. for 2 hrs. Thereafter, 2 mol/L aqueous HCl(0.758 mL, 1.515 mmol) was added and the mixture was poured intochloroform and water. The aqueous portion was extracted twice withchloroform. The organic portions were combined, dried (over MgSO₄),filtered, and concentrated to dryness. The residue was chromatographedon a silica gel column eluted with n-hexane and EtOAc containing 5% TEAto provide 180 mg of Substituted Benzimidazole-Type Piperidine CompoundZA35,(1-((1R,1′R,3r,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methanol(yield 91%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA35was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA35: ¹H-NMR: δ_(H)(ppm, 400 MHz, CDCl₃): 1.13-2.26 (m, 24H), 3.49-3.78 (m, 4H), 4.85 (m,1H), 4.92 (s, 2H), 7.26 (m, 2H), 7.67 (m, 1H), 7.74 (m, 1H); LC/MS:m/z=394.4 [M+H]⁺ (Calc.: 393).

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA35(100 mg, 0.254 mmol) in DCM (3.0 mL) was added manganese dioxide (88 mg,1.02 mmol, Sigma Aldrich). The resulting reaction mixture was heated toreflux and refluxed with stirring for 3 hrs. Thereafter, the insolublematerial was removed by filtration through CELITE. The filtrate wasconcentrated and dried under reduced pressure to provide 86 mg ofSubstituted Benzimidazole-Type Piperidine Compound ZA36,1-((1R,1′R3r,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazole-2-carbaldehyde(yield 86%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA36was confirmed using ¹H-NMR.

Substituted Benzimidazole-Type Piperidine Compound ZA36: ¹H-NMR: δ_(H)(ppm, 400 MHz, CDCl₃): 1.13-2.41 (m, 24H), 3.49-3.68 (m, 3H), 5.90 (m,1H), 7.35-7.50 (m, 2H), 7.79 (m, 1H), 7.91 (m, 1H), 10.1 (s, 1H).

To a solution of Substituted Benzimidazole-Type Piperidine Compound ZA36(84 mg, 0.215 mmol) in MeOH (1.5 mL) and water (0.5 mL) was added2-(aminooxy)acetic acid hemihydrochloride (28 mg, 0.257 mmol, SigmaAldrich). The resulting reaction mixture was heated to reflux andrefluxed with stirring for 2 hrs. Thereafter, a 2 mol/L aqueous NaOHsolution (0.13 mL) was added followed by evaporation to dryness. Theresulting residue was diluted with chloroform and MeOH. The solution wasdried (over MgSO₄), filtered, and concentrated to dryness. The residuewas chromatographed on a silica gel column eluted with DCM and MeOHcontaining 10% NH₄OH to provide 42 mg of Substituted Benzimidazole-TypePiperidine Compound ZA37,2-(((E)-((1-((1R,1′R,3r,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)methylene)amino)oxy)aceticacid (yield 42%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA37was confirmed using ¹H-NMR and LC/MS.

Substituted Benzimidazole-Type Piperidine Compound ZA37: ¹H-NMR: δ_(H)(ppm, 400 MHz, CDCl₃): 1.35-2.65 (m, 22H), 2.98 (m, 2H), 4.08-4.30 (m,3H), 4.69 (s, 2H), 6.65 (m, 1H), 7.31 (m, 2H), 7.59 (m, 1H), 7.80 (m,1H), 8.20 (s, 1H); LC/MS: m/z=465.3 [M+H]⁺ (Calc.: 464).

5.15 Example 15 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where t is 0 and the Q_(x) Ring is a 5- or 6-MemberedHeterocycle

Using procedures similar to those described in Example 1, the followingSubstituted Benzimidazole-Type Piperidine Compounds were prepared fromCompound 66. The co-reactant compounds are commercially available from,e.g., Sigma-Aldrich, or can be prepared by methods known to the art.

H27(b):1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-((R)-pyrrolidin-2-yl)-1H-benzo[d]imidazole.

H27(b): ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.74 (m, 1H), 7.67 (m, 1H), 7.27 (m,2H), 4.95 (m, 1H), 4.50 (m, 1H), 3.69 (m, 2H), 3.23 (m, 1H), 3.02 (m,1H), 2.43-2.23 (m, 8H), 2.06-1.81 (m, 10H), 1.79-1.56 (m, 6H), 1.50 (m,2H), 1.32 (m, 2H); MS: m/z=447.3 [M+H]⁺.

ZA38:4-(((R)-2-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)sulfonyl)-3,5-dimethylisoxazole.

ZA38: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.80 (m, 1H), 7.60 (m, 1H), 7.37 (m,2H), 5.42 (m, 2H), 4.31 (m, 2H), 3.91 (m, 1H), 3.62 (m, 2H), 2.70 (m,3H), 2.44 (m, 3H), 2.30 (s, 3H), 2.10 (m, 51H), 2.00 (s, 3H), 1.96 (m,3H), 1.77 (m, 6H), 1.67 (m, 4H), 1.50 (m, 5H); MS: m/z=606.3 [M+H]⁺.

ZA39:1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-tetrazol-5-yl)-1H-benzo[d]imidazole.

ZA39: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.77 (m, 1H), 7.67 (m, 1H), 7.33 (m,2H), 5.72 (m, 1H), 4.31 (m, 2H), 3.90 (m, 1H), 2.75 (m, 4H), 2.44 (m,3H), 2.10 (m, 3H), 1.94 (m, 4H), 1.76 (m, 7H), 1.51 (m, 5H); MS:m/z=446.3 [M+H]⁺.

ZA40:1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole.

ZA40: ¹H-NMR: δ_(H) (ppm, CD₃OD): 8.39 (s, 1H), 7.77 (m, 1H), 7.68 (m,1H), 7.25 (m, 2H), 5.52 (m, 1H), 3.54 (br, 2H), 3.05 (m, 1H), 2.34-2.12(m, 7H), 1.87-1.30 (m, 14H), 1.21 (m, 4H); MS: m/z=445.4 [M+H]⁺.

ZA41:1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(pyrazin-2-yl)-1H-benzo[d]imidazole.

ZA41: ¹H-NMR: δ_(H) (ppm, CD₃OD): 9.37 (s, 1H), 9.08 (s, 1H), 9.00 (s,1H), 8.42 (d, J=8 Hz, 1H), 8.04 (d, J=8 Hz, 1H), 7.79 (m, 2H), 6.32 (m,1H), 4.33 (m, 2H), 3.91 (m, 1H), 2.95 (m, 2H), 2.76 (m, 2H), 2.43 (m,3H), 2.13 (m, 5H), 1.97-1.59 (m, 10H), 1.48 (m, 4H); MS: m/z=456.3[M+H]⁺.

ZA42:1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazole.

ZA42: ¹H-NMR: δ_(H) (ppm, CD₃OD): 8.75 (s, 1H), 8.35 (s, 1H), 7.86 (m,1H), 7.75 (m, 1H), 7.34 (m, 2H), 5.34 (m, 1H), 4.48 (m, 3H), 4.08 (s,3H), 3.57 (br, s, 2H), 3.05 (m, 1H), 2.36 (m, 5H), 2.23 (m, 5H),1.92-1.46 (m, 8H), 1.39 (m, 2H), 1.26 (m, 3H); MS: m/z=486.3 [M+H]⁺.

5.16 Example 16 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where t is 1 and the Q_(x) Ring is a 5- or 6-MemberedHeterocycle

Using procedures similar to those described in Example 1, the followingSubstituted Benzimidazole-Type Piperidine Compounds were prepared fromCompound 66. The co-reactant compounds are commercially available from,e.g., Sigma-Aldrich, or can be prepared by methods known to the art.

ZA43:N-(2-((S)-2-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-1-yl)ethyl)methanesulfonamide.

ZA43: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.67 (m, 1H), 7.49 (m, 1H), 7.12 (m,2H), 4.86 (m, 1H), 3.57 (m, 2H), 3.17-2.84 (m, 81H), 2.79 (s, 3H),2.46-2.11 (m, 8H), 1.90-1.47 (m, 16H), 1.41 (m, 2H), 1.28-1.07 (m, 4H);MS: m/z=582.3 [M+H]⁺.

ZA44:2-((S)-2-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-1-yl)-N,N-diethylacetamide.

ZA44: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.64 (d, J=8 Hz, 1H), 7.50 (d, J=8 Hz,1H), 7.15 (m, 2H), 4.88 (br, s, 1H), 3.62 (m, 3H), 3.28 (m, 2H), 3.05(m, 4H), 2.81 (m, 1H), 2.42 (m, 1H), 2.25 (m, 6H), 1.96-1.36 (m, 14H),1.15 (m, 3H), 0.98 (m, 6H); MS: m/z=574.5 [M+H]⁺.

ZA45:2-((S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-1-yl)aceticacid.

ZA45: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.80-7.71 (m, 1H), 7.66-7.59 (m, 1H),7.36-7.23 (m, 2H), 5.54-5.38 (m, 1H), 4.33-4.15 (m, 2H), 3.96-3.78 (m,1H), 3.69-3.53 (m, 4H), 3.17-2.88 (m, 4H), 2.77-2.35 (m, 8H), 2.33-1.34(m, 23H); MS: m/z=533.4 [M+H]⁺.

ZA46:2-((S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-1-yl)aceticacid.

ZA46: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.79-7.73 (m, 1H), 7.72-7.66 (m, 1H),7.34-7.21 (m, 2H), 5.13-4.97 (m, 1H), 3.96-3.82 (m, 2H), 3.82-3.71 (m,2H), 3.71-3.54 (m, 2H), 3.53-3.04 (m, 6H), 2.57-2.29 (m, 8H), 2.08-1.37(m, 20H); MS: m/z=519.3 [M+H]⁺.

ZA47:3-((S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-1-yl)propanoicacid.

ZA47: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.83-7.74 (m, 1H), 7.68-7.61 (m, 1H),7.39-7.25 (m, 2H), 5.54-5.33 (m, 1H), 4.40-4.27 (m, 2H), 4.00-3.71 (m,2H), 3.55-3.33 (m, 2H), 3.28-2.95 (m, 4H), 2.89-2.33 (m, 10H), 2.24-1.27(m, 24H); MS: m/z=547.3 [M+H]⁺.

ZA48:3-((S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-1-yl)propanoicacid.

ZA48: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.87-7.65 (m, 2H), 7.48-7.21 (m, 2H),5.82-5.56 (m, 1H), 4.47-4.26 (m, 2H), 4.15-3.83 (m, 1H), 3.79-3.56 (m,2H), 3.55-3.22 (m, 6H), 3.22-3.03 (m, 1H), 2.85-2.51 (m, 6H), 2.55-2.28(m, 4H), 2.28-2.08 (m, 4H), 2.08-1.44 (m, 16H); MS: m/z=533.4 [M+H]⁺.

ZA49:N-(2-((S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]midazol-2-yl)methyl)piperidin-1-yl)ethyl)methanesulfonamide.

ZA49: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.83-7.69 (m, 1H), 7.65-7.54 (m, 1H),7.33-7.17 (m, 2H), 4.97-4.79 (m, 1H), 3.77-3.57 (m, 2H), 3.27-3.09 (m,3H), 3.00-2.77 (m, 7H), 2.59-2.46 (m, 2H), 2.45-2.00 (m, 9H), 2.00-1.41(m, 18H), 1.41-1.04 (m, 5H); MS: m/z=596.4 [M+H]⁺.

ZA50:N-(2-((S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-1-yl)ethyl)methanesulfonamide.

ZA50: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81-7.71 (m, 1H), 7.64-7.57 (m, 1H),7.32-7.17 (m, 2H), 4.97-4.81 (m, 1H), 3.72-3.60 (m, 2H), 3.24-3.11 (m,3H), 3.09-2.99 (m, 2H), 2.98-2.91 (m, 3H), 2.91-2.56 (m, 7H), 2.50-2.17(m, 8H ), 2.18-2.01 (m, 1H), 2.01-1.41 (m, 15H), 1.42-1.19 (m, 4H); MS:m/z=582.3 [M+H]⁺.

ZA51:2-((S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-1-yl)-N,N-diethylacetamide.

ZA51: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81-7.70 (m, 1H), 7.65-7.53 (m, 1H),7.31-7.15 (m, 2H), 4.97-4.82 (m, 1H), 3.76-3.59 (m, 2H), 3.52-3.07 (m,6H), 2.99-2.69 (m, 4H), 2.50-2.04 (m, 9H), 2.02-1.42 (m, 19H), 1.42-1.01(m, 9H), 1.01-0.83 (m, 3H); MS: m/z=588.5 [M+H]⁺.

ZA52:2-((S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-1-yl)-N,N-diethylacetamide.

ZA52: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81-7.70 (m, 1H), 7.67-7.53 (m, 1H),7.34-7.16 (m, 2H), 4.97-4.82 (m, 1H), 3.74-3.59 (m, 2H), 3.48-3.33 (m,4H), 3.27-3.14 (m, 1H), 3.10-2.99 (m, 2H), 2.95-2.85 (m, 1H), 2.85-2.65(m, 3H), 2.54-2.00 (m, 9H), 1.99-1.40 (m, 16H), 1.40-1.23 (m, 4H),1.25-1.15 (m, 4H), 1.15-0.98 (m, 4H); MS: m/z=574.3 [M+H]⁺.

ZA53:(S)-5-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-2-one.

ZA53: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.80 (m, 1H), 7.70 (m, 1H), 7.33 (m,2H), 5.59 (br, s, 1H), 4.35 (m, 3H), 4.00 (m, 1H), 3.31 (m, 2H),2.83-2.31 (m, 9H), 2.23-1.67 (m, 14H), 1.60 (m, 4H); MS: m/z=475.4[M+H]⁺.

ZA54:2-((S)-2-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-1-yl)aceticacid.

ZA54: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.95 (d, J=8 Hz, 1H), 7.84 (d, J=8 Hz,1H), 7.62 (m, 2H), 6.10 (m, 1H), 4.67 (m, 1H), 4.54 (m, 1H), 4.42 (m,2H), 4.32 (m, 2H), 4.09-3.83 (m, 3H), 3.41 (m, 1H), 2.93 (m, 1H), 2.78(m, 1H), 2.63 (m, 2H), 2.40 (m, 2H), 2.35-2.00 (m, 7H), 1.98-1.76 (m,7H), 1.69 (m, 4H), 1.41 (m, 5H); MS: m/z=519.3 [M+H]⁺.

ZA55:(S)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)morpholine.

ZA55: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz,1H), 7.34 (m, 2H), 5.49 (br, s, 1H), 4.21 (m, 2H), 4.02 (m, 1H), 3.95(m, 1H), 3.80 (m, 1H), 3.74 (m, 1H), 3.64 (m, 2H), 3.27 (m, 2H), 3.19(m, 2H), 2.65 (m, 2H), 2.55 (m, 2H), 2.46 (m, 3H), 2.17-1.52 (m, 19H);MS: m/z=477.3 [M+H]⁺.

ZA56:(R)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)morpholine.

ZA56: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81 (m, 1H), 7.70 (m, 1H), 7.34 (m,2H), 5.65 (br, s, 1H), 4.27 (m, 2H), 4.02 (m, 1H), 3.94 (m, 1H), 3.87(m, 1H), 3.75 (m, 1H), 3.34 (m, 2H), 3.21 (m, 1H), 2.64 (m, 4H), 2.47(m, 3H), 2.20-1.51 (m, 19H); MS: m/z=477.3 [M+H]⁺.

ZA57:(R)-3-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-4-((1-methyl-1H-imidazol-2-yl)methyl)morpholine.

ZA57: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz,1H), 7.43 (m, 2H), 7.36 (m, 2H), 5.50 (m, 1H), 4.30 (m, 2H), 4.12 (m,2H), 3.89 (m, 1H), 3.76 (s, 3H), 3.70 (m, 2H), 3.50 (m, 1H), 3.41 (m,3H), 2.98 (m, 1H), 2.64 (m, 4H), 2.38 (m, 4H), 2.01 (m, 5H), 1.75 (m,9H), 1.48 (m, 5H); MS: m/z=571.3 [M+H]⁺.

ZA58:3-((S)-2-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)pyrrolidin-1-yl)propanoicacid.

ZA58: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.70 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.8Hz, 1H), 7.24 (m, 2H), 5.48 (br, s, 1H), 4.28 (m, 2H), 4.12 (m, 1H),3.86 (m, 1H), 3.71 (s, 2H), 3.61 (m, 1H), 3.47 (m, 1H), 3.31 (m, 2H),2.96 (m, 2H), 2.78-2.47 (m, 5H), 2.35 (m, 4H), 2.06 (m, 4H), 1.98-1.61(m, 9H), 1.48 (m, 5H), 1.22 (m, 2H); MS: m/z=533.4 [M+H]⁺.

ZA59:2-((S)-2-((1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)piperidin-1-yl)aceticacid.

ZA59: ¹H-NMR: δ_(H) (ppm, CD₃OD): 8.04 (d, J=8 Hz, 1H), 7.81 (d, J=8 Hz,1H), 7.62 (m, 2H), 5.92 (br, s, 1H), 4.60 (m, 3H), 4.24 (m, 3H), 3.91(m, 2H), 3.61 (m, 1H), 3.28 (m, 1H), 2.80 (m, 3H), 2.35 (m, 4H), 1.99(m, 6H), 1.77 (m, 10H), 1.48 (m, 5H); MS: m/z=533.4 [M+H]⁺.

ZA60:1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(pyrazin-2-ylmethyl)-1H-benzo[d]imidazole.

ZA60: ¹H-NMR: δ_(H) (ppm, CD₃OD): 8.99 (s, 1H), 8.69 (m, 1H), 8.58 (m,1H), 8.08 (m, 1H), 7.79 (m, 1H), 7.62 (m, 2H), 6.13 (m, 1H), 4.25 (m,2H), 3.86 (m, 1H), 2.70 (m, 4H), 2.33 (m, 3H), 2.03 (m, 5H), 1.88 (m,2H), 1.88 (m, 2H), 1.84-1.60 (m, 8H), 1.43 (m, 4H); MS: m/z=470.4[M+H]⁺.

ZA61:1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-((5-methyl-4H-1,2,4-triazol-3-yl)methyl)-1H-benzo[d]imidazole.

ZA61: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.67 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz,1H), 7.17 (m, 2H), 4.81 (m, 1H), 4.32 (s, 2H), 3.61 (m, 1H), 2.30 (s,3H), 2.22 (m, 7H), 1.87-1.64 (m, 6H), 1.56 (m, 2H), 1.46 (m, 3H), 1.30(m, 6H); MS: m/z=473.2 [M+H]⁺.

ZA62:2-((1H-tetrazol-5-yl)methyl)-1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazole.

ZA62: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.68 (m, 1H), 7.61 (m, 1H), 7.57 (m,1H), 7.27 (m, 2H), 5.25 (m, 1H), 4.51 (s, 2H), 4.22 (m, 2H), 3.89 (m,1H), 2.52 (m, 4H), 2.26 (m, 3H), 2.06 (m, 5H), 1.90 (m, 3H), 1.78 (m,5H), 1.48 (m, 5H); MS: m/z=460.4 [M+H]⁺.

5.17 Example 17 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where t is 0 and the Q_(x) Ring is a 5- or 6-MemberedHeterocycle

Using procedures similar to those described in Example 1, the followingSubstituted Benzimidazole-Type Piperidine Compounds were prepared fromCompound 56. The co-reactant compounds are commercially available from,e.g., Sigma-Aldrich, or can be prepared by methods known to the art.

ZA63:(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(5-methoxypyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).

ZA63: ¹H-NMR: δ_(H) (ppm, CD₃OD): 8.78-8.69 (m, 1H), 8.42-8.33 (m, 1H),7.93-7.82 (m, 1H), 7.77-7.68 (m, 1H), 7.43-7.25 (m, 2H), 5.47-5.29 (m,1H), 4.15 (s, 3H), 3.70-3.41 (m, 2H), 2.45-2.26 (m, 6H), 2.06-1.83 (m,6H), 1.83-1.72 (m, 1H), 1.72-1.45 (m, 7H), 1.45-1.32 (m, 2H), 1.32-1.16(m, 2H); MS: m/z=472.4 [M+H]⁺.

ZA64:(1R,1′R,3r,3′R,5S,5′S)-3′-(2-(pyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)-9′-aza-3,9′-bi(bicyclo[3.3.1]nonane).

ZA64: ¹H-NMR: δ_(H) (ppm, CD₃OD): 9.44-9.39 (m, 1H), 9.14-9.07 (m, 1H),9.04-8.99 (m, 1H), 8.45-8.37 (m, 1H), 8.09-8.00 (m, 1H), 7.89-7.74 (m,2H), 6.26-6.10 (m, 1H), 4.38-4.19 (m, 3H), 2.99-2.87 (m, 2H), 2.82-2.70(m, 2H), 2.43-2.27 (m, 1H), 2.27-2.06 (m, 8H), 2.06-1.96 (m, 1H),1.84-1.45 (m, 10H); MS: m/z=442.2 [M+H]⁺.

ZA65:5-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)-2,4-dimethylthiazole.

ZA65: ¹H-NMR: δ_(H) (ppm, CD₃OD): 8.25-8.17 (m, 1H), 8.04-7.98 (m, 1H),7.89-7.82 (m, 1H), 7.82-7.74 (m, 1H), 6.02-5.88 (m, 1H), 4.37-4.17 (m,3H), 3.16 (s, 3H), 2.88-2.66 (m, 4H), 2.66 (s, 3H), 2.42-2.23 (m, 3H),2.23-1.99 (m, 7H), 1.87-1.77 (m, 2H), 1.77-1.60 (m, 6H), 1.60-1.47 (m,2H); MS: m/z=475.2 [M+H]⁺.

5.18 Example 18 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where t is 0 and the Q_(x) Ring is a 5-Membered Heterocycle

Using procedures similar to those described in Example 14, the followingSubstituted Benzimidazole-Type Piperidine Compounds were prepared fromCompound 56. The co-reactant compounds are commercially available from,e.g., Sigma-Aldrich, or can be prepared by methods known to the art.

ZA66:5-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)isoxazole.

ZA66: ¹H-NMR: δ_(H) (ppm, CD₃OD): 8.75-8.69 (m, 1H), 8.00-7.91 (m, 1H),7.84-7.77 (m, 1H), 7.54-7.37 (m, 2H), 7.17-7.10 (m, 1H), 5.61-5.44 (m,1H), 4.42-3.83 (m, 3H), 2.81-2.52 (m, 4H), 2.52-2.02 (m, 8H), 2.02-1.43(m, 12H); MS: m/z=431.3 [M+H]⁺.

ZA67:3-(1-((1R,1′R,3r,3′R,5S,5′S)-[3,9′-bi(9′-azabicyclo[3.3.1]nonan)]-3′-yl)-1H-benzo[d]imidazol-2-yl)-5-methylisoxazole.

ZA67: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.95-7.89 (m, 1H), 7.86-7.76 (m, 1H),7.54-7.33 (m, 2H), 6.89-6.72 (m, 1H), 6.48-6.30 (m, 1H), 4.46-4.13 (m,3H), 2.93-2.51 (m, 9H), 2.51-1.55 (m, 18H); MS: m/z=445.4 [M+H]⁺.

5.19 Example 19 Synthesis of Substituted Benzimidazole-Type PiperidineCompound ZA68 Where t is 0 and the Q_(x) Ring is a 5-MemberedHeterocycle

To a solution of Compound 66 (0.184 g, 0.5 mmol) in EtOH (1 mL) at atemperature of about 25° C. was added 1H-imidazole-4-carbaldehyde(Compound 67, 0.048 g, 0.5 mmol, Sigma-Aldrich) and 40% aq. NaHSO₃ (1.1mL). The resulting reaction mixture was then irradiated for 60 min at150° C. using a BIOTAGE Initiator microwave synthesizer apparatus(Biotage, LLC, Charlotte, N.C.) operating at 2.45 GHz and a maximum of400 Watts. Thereafter, the mixture was evaporated to dryness underreduced pressure to provide a product which was chromatographed on aflash column eluted with a gradient of from 0:100 MeOH (10% NH₄OH):DCMto 30:70 MeOH (10% NH₄OH):DCM. The fractions containing the product werecombined and, under reduced pressure, evaporated and dried to provideSubstituted Benzimidazole-Type Piperidine Compound ZA68,1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-imidazol-4-yl)-1H-benzo[d]imidazole(yield 40%).

The identity of Substituted Benzimidazole-Type Piperidine Compound ZA68was confirmed using ¹H-NMR and MS.

ZA68: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.83 (m, 2H), 7.68 (m, 1H), 7.62 (m,1H), 7.29 (m, 2H), 5.46 (br, s, 1H), 3.65 (br, s, 2H), 3.17 (m, 1H),2.48-2.22 (m, 7H), 1.97-1.49 (m, 12H), 1.43 (m, 2H), 1.29 (m, 4H); MS:m/z=444.3 [M+H]⁺.

5.20 Example 20 Synthesis of Substituted Benzimidazole-Type PiperidineCompounds Where t is 0 and the Q_(x) Ring is a 5- or 6-MemberedHeterocycle

Using procedures similar to those described in Example 19, the followingSubstituted Benzimidazole-Type Piperidine Compounds were prepared fromCompound 66. The co-reactant compounds are commercially available from,e.g., Sigma-Aldrich, or can be prepared by methods known to the art.

ZA69:1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(1H-pyrazol-3-yl)-1H-benzo[d]imidazole.

ZA69: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.95 (m, 2H), 7.74 (m, 1H), 7.52 (m,2H), 7.01 (m, 1H), 5.78 (m, 1H), 4.24 (m, 2H), 3.87 (m, 1H), 2.85 (m,2H), 2.65 (m, 2H), 2.42 (m, 3H), 2.02 (m, 5H), 1.80 (m, 4H), 1.66 (m,5H), 1.49 (m, 5H); MS: m/z=444.3 [M+H]⁺.

ZA70:1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-2-(4-chloro-1-methyl-1H-pyrazol-3-yl)-1H-benzo[d]imidazole.

ZA70: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.98 (s, 1H), 7.85 (m, 1H), 7.73 (m,1H), 7.43 (m, 2H), 5.38 (m, 1H), 4.21 (br, 2H), 3.97 (s, 3H), 3.84 (m,1H), 2.64 (m, 4H), 2.35 (m, 2H), 2.17-1.56 (m, 16H), 1.45 (m, 4H); MS:m/z=492.4 [M+H]⁺.

ZA71:6-(1-((1R,3R,5S)-9-((1R,6S,8r)-bicyclo[4.3.1]decan-8-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-1H-benzo[d]imidazol-2-yl)pyrimidine-2,4(1H,3H)-dione.

ZA71: ¹H-NMR: δ_(H) (ppm, CD₃OD): 7.81 (m, 1H), 7.73 (m, 1H), 7.38 (m,2H), 5.91 (s, 1H), 5.14 (m, 1H), 4.22 (m, 2H), 3.87 (m, 1H), 2.64 (m,4H), 2.38 (m, 3H), 2.03 (m, 5H), 1.76 (m, 7H), 1.51 (m, 7H); MS:m/z=488.3 [M+H]⁺.

5.21 Example 21 In vitro ORL-1 Receptor Binding Assay

ORL-1 Receptor Binding Assay Procedures: Membranes from recombinantHEK-293 cells expressing the human opioid receptor-like receptor (ORL-1)(Receptor Biology) were prepared by lysing cells in ice-cold hypotonicbuffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 mL/10 cm dish) followedby homogenization with a tissue grinder/Teflon pestle. Membranes werecollected by centrifugation at 30,000×g for 15 min at 4° C. and pelletsresuspended in hypotonic buffer to a final concentration 1-3 mg/mL.Protein concentrations were determined using the BioRad protein assayreagent with bovine serum albumen as a standard. Aliquots of the ORL-1receptor membranes were stored at −80° C.

Radioligand binding assays (screening and dose-displacement) used 0.1 nM[³H]-nociceptin (NEN; 87.7 Ci/mmole) with 10-20 μg membrane protein in afinal volume of 500 μL binding buffer (10 mM MgCl₂, 1 mM EDTA, 5% DMSO,50 mM HEPES, pH 7.4). Non-specific binding was determined in thepresence of 10 nM unlabeled nociceptin (American Peptide Company). Allreactions were performed in 96-deep well polypropylene plates for 1 h atabout 25° C. Binding reactions were terminated by rapid filtration onto96-well Unifilter GF/C filter plates (Packard) presoaked in 0.5%polyethylenimine (Sigma-Aldrich). Harvesting was performed using a96-well tissue harvester (Packard) followed by three filtration washeswith 500 μL ice-cold binding buffer. Filter plates were subsequentlydried at 50° C. for 2-3 hrs. Fifty L/well scintillation cocktail(BetaScint; Wallac) was added and plates were counted in a PackardTop-Count for 1 min/well. The data from screening and dose-displacementexperiments were analyzed using Microsoft Excel and the curve fittingfunctions in GraphPad PRISM™, v. 3.0, respectively, or an in-housefunction for one-site competition curve-fitting.

ORL-1 Receptor Binding Data: An Substituted Benzimidazole-TypePiperidine Compound has a binding affinity (K_(i)) for the human ORL-1receptor of about 1000 nM or less in one embodiment, or about 500 nM orless in another embodiment. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a K_(i) (nM) of about 300 orless for binding to ORL-1 receptors. In one embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has a K_(i) (nM) of about 100 orless. In another embodiment, a Substituted Benzimidazole-Type PiperidineCompound of the disclosure has a K_(i) (nM) of about 35 or less. Inanother embodiment, a Substituted Benzimidazole-Type Piperidine Compoundof the disclosure has a K_(i) (nM) of about 20 or less. In anotherembodiment, a Substituted Benzimidazole-Type Piperidine Compound of thedisclosure has a K_(i) (nM) of about 15 or less. In another embodiment,a Substituted Benzimidazole-Type Piperidine Compound of the disclosurehas a K_(i) (nM) of about 10 or less. In another embodiment, aSubstituted Benzimidazole-Type Piperidine Compound of the disclosure hasa K_(i) (nM) of about 4 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has a K_(i)(nM) of about 1 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has a K_(i)(nM) of about 0.4 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound of the disclosure has a K_(i)(nM) of about 0.1 or less.

5.22 Example 22 In vitro ORL-1 Receptor Functional Assay

ORL-1 Receptor [³⁵S]GTPγS Binding Assay Procedures: Membranes fromrecombinant HEK-293 cells expressing the human opioid receptor-like(ORL-1) (Receptor Biology) were prepared by lysing cells in ice-coldhypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 mL/10 cm dish)followed by homogenization with a tissue grinder/Teflon pestle.Membranes were collected by centrifugation at 30,000×g for 15 min at 4°C., and pellets resuspended in hypotonic buffer to a final concentrationof 1-3 mg/mL. Protein concentrations were determined using the BioRadprotein assay reagent with bovine serum albumen as a standard. Aliquotsof the ORL-1 receptor membranes were stored at −80° C.

Functional binding assays were conducted as follows. ORL-1 membranesolution was prepared by sequentially adding final concentrations of0.066 μg/μL ORL-1 membrane protein, 10 μg/mL saponin, 3 μM GDP and 0.20nM [35S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES,pH 7.4) on ice. The prepared membrane solution (190 L/well) wastransferred to 96-shallow well polypropylene plates containing 10 μL of20× concentrated stock solutions of agonist/nociceptin prepared in DMSO.Plates were incubated for 30 min at about 25° C. with shaking. Reactionswere terminated by rapid filtration onto 96-well Unifilter GF/B filterplates (Packard) using a 96-well tissue harvester (Packard) and followedby three filtration washes with 200 μL ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently driedat 50° C. for 2-3 hrs. Fifty μL/well scintillation cocktail (BetaScint;Wallac) was added and plates were counted in Packard Top-Count for 1min/well. Data are analyzed using the sigmoidal dose-response curvefitting functions in GraphPad PRISM v. 3.0, or an in-house function fornon-linear, sigmoidal dose-response curve-fitting.

ORL-1 Receptor Functional Data: ORL-1 GTP EC₅₀ is the concentration of acompound providing 50% of the maximal response for the compound at anORL-1 receptor. In one embodiment, a Substituted Benzimidazole-TypePiperidine Compound has an ORL-1 GTP EC₅₀ (nM) of about 5000 or less tostimulate ORL-1 receptor function. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 1000 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 100 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 80 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 50 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 35 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 15 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 10 or less. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP EC₅₀ (nM) ofabout 4 or less. In another embodiment, a Substituted Benzimidazole-TypePiperidine Compound has an ORL-1 GTP EC₅₀ (nM) of about 1 or less. Inanother embodiment, a Substituted Benzimidazole-Type Piperidine Compoundhas an ORL-1 GTP EC₅₀ (nM) of about 0.4 or less. In another embodiment,a Substituted Benzimidazole-Type Piperidine Compound has an ORL-1 GTPEC₅₀ (nM) of about 0.1 or less.

ORL-1 GTP Emax (%) is the maximal effect elicited by a compound relativeto the effect elicited by nociceptin, a standard ORL-1 agonist. In oneembodiment, a Substituted Benzimidazole-Type Piperidine Compound has anORL-1 GTP Emax (%) of about 50% or greater. In another embodiment, aSubstituted Benzimidazole-Type Piperidine Compound has an ORL-1 GTP Emax(%) of about 75% or greater. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP Emax (%) ofabout 85% or greater. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP Emax (%) ofabout 95% or greater. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP Emax (%) ofabout 100% or greater. In another embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has an ORL-1 GTP Emax (%) ofabout 110% or greater. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound acting as a partial agonist hasan ORL-1 GTP Emax (%) of less than about 10%. In one embodiment, partialagonist Substituted Benzimidazole-Type Piperidine Compounds has an ORL-1GTP Emax (%) of less than about 20%. In another embodiment, partialagonist Substituted Benzimidazole-Type Piperidine Compounds has an ORL-1GTP Emax (%) of less than about 30%. In another embodiment, partialagonist Substituted Benzimidazole-Type Piperidine Compounds has an ORL-1GTP Emax (%) of less than about 40%. In another embodiment, partialagonist Substituted Benzimidazole-Type Piperidine Compounds has an ORL-1GTP Emax (%) of less than about 50%.

5.23 Example 23 In vitro Mu-opioid Receptor Binding Assays

μ-Opioid Receptor Binding Assay Procedures: Radioligand binding assayswere conducted using freshly thawed membranes expressing humanμ-receptors (Perkin Elmer, Shelton, Conn.). Radioliganddose-displacement binding assays for human μ-opioid receptors used 0.2nM[³H]-diprenorphine (NEN, Boston, Mass.), with 5-20 mg membraneprotein/well in a final volume of 500 μL binding buffer (10 mM MgCl₂, 1mM EDTA, 5% DMSO, 50 mM HEPES, pH 7.4). Reactions were carried out inthe absence or presence of increasing concentrations of unlabelednaloxone. All reactions were conducted in 96-deep well polypropyleneplates for 1-2 hrs at about 25° C. Binding reactions were terminated byrapid filtration onto 96-well Unifilter GF/C filter plates (Packard,Meriden, Conn.) presoaked in 0.5% polyethylenimine using a 96-welltissue harvester (Brandel, Gaithersburg, Md.) followed by performingthree filtration washes with 500 μL of ice-cold binding buffer. Filterplates were subsequently dried at 50° C. for 2-3 hrs. BetaScintscintillation cocktail (Wallac, Turku, Finland) was added (50 μL/well),and plates were counted using a Packard Top-Count for 1 min/well. Thedata were analyzed using the one-site competition curve fittingfunctions in GraphPad PRISM v. 3.0 (San Diego, Calif.), or an in-housefunction for one-site competition curve-fitting.

μ-Opioid Receptor Binding Data: In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a K_(i) (nM) of about 3000 orless for binding to μ-opioid receptors, or about 1000 or less, or about650 or less, or about 525 or less, or about 250 or less, or about 100 orless, or about 10 or less, or about 1 or less, or about 0.1 or less.

5.24 Example 24 In vitro Mu-Opioid Receptor Functional Assays

μ-Opioid Receptor Functional Assay Procedures: [³⁵S]GTPγS functionalassays were conducted using freshly thawed membranes expressing humanμ-receptors. Assay reactions were prepared by sequentially adding thefollowing reagents to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mMHEPES, pH 7.4) on ice (final concentrations indicated): membrane protein(0.026 mg/mL), saponin (10 mg/mL), GDP (3 mM) and [³⁵S]GTPγS (0.20 nM;NEN). The prepared membrane solution (190 μL/well) was transferred to96-shallow well polypropylene plates containing 10 μL of 20×concentrated stock solutions of the agonist DAMGO ([D-Ala2,N-methyl-Phe4 Gly-ol5]-enkephalin) prepared in DMSO. Plates wereincubated for 30 min at about 25° C. with shaking. Reactions wereterminated by rapid filtration onto 96-well Unifilter GF/B filter plates(Packard, Meriden, Conn.) using a 96-well tissue harvester (Brandel,Gaithersburg, Md.) followed by three filtration washes with 200 μL ofice-cold wash buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filterplates were subsequently dried at 50° C. for 2-3 hrs. BetaScintscintillation cocktail (Wallac, Turku, Finland) was added (50 μL/well)and plates were counted using a Packard Top-Count for 1 min/well. Datawere analyzed using the sigmoidal dose-response curve fitting functionsin GraphPad PRISM v. 3.0, or an in-house function for non-linear,sigmoidal dose-response curve-fitting.

μ-Opioid Receptor Functional Data: μ GTP EC₅₀ is the concentration of acompound providing 50% of the maximal response for the compound at aμ-opioid receptor. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a GTP EC₅₀ (nM) of about 5000or less, or about 4100 or less, or about 3100 or less, or about 2000 orless, or about 1000 or less, or about 100 or less, or about 10 or less,or about 1 or less, or about 0.4 or less, or about 0.1 or less.

μ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by DAMGO, a standard μ agonist. In certainembodiments, a Substituted Benzimidazole-Type Piperidine Compound has aμ GTP Emax (%) of about 10% or greater, or about 20% or greater, orabout 50% or greater, or about 65% or greater, or about 75% or greater,or about 88% or greater, or about 100% or greater. In other embodiments,a Substituted Benzimidazole-Type Piperidine Compound has a GTP Emax (%)of about 10% or less, or about 5% or less, or about 2% or less.

5.25 Example 25 In Vitro Kappa-Opioid Receptor Binding Assays

κ-Opioid Receptor Binding Assay Procedures: Membranes from recombinantHEK-293 cells expressing the human kappa opioid receptor (kappa) (clonedin house) were prepared by lysing cells in ice cold hypotonic buffer(2.5 mM MgCl₂, 50 mM HEPES, pH 7.4) (10 mL/10 cm dish) followed byhomogenization with a tissue grinder/Teflon pestle. Membranes werecollected by centrifugation at 30,000×g for 15 min at 4° C. and pelletsresuspended in hypotonic buffer to a final concentration of 1-3 mg/mL.Protein concentrations were determined using the BioRad protein assayreagent with bovine serum albumen as a standard. Aliquots of kappareceptor membranes were stored at −80° C.

Radioligand dose displacement assays used 0.4-0.8 nM [³H]-U69,593 (NEN;40 Ci/mmole) with 10-20 μg membrane protein (recombinant kappa opioidreceptor expressed in HEK 293 cells; in-house prep) in a final volume of200 μL binding buffer (5% DMSO, 50 mM Trizma base, pH 7.4). Non-specificbinding was determined in the presence of 10 μM unlabeled naloxone orU69,593. All reactions were performed in 96-well polypropylene platesfor 1 h at a temperature of about 25° C. Binding reactions weredetermined by rapid filtration onto 96-well Unifilter GF/C filter plates(Packard) presoaked in 0.5% polyethylenimine (Sigma-Aldrich). Harvestingwas performed using a 96-well tissue harvester (Packard) followed byfive filtration washes with 200 μL ice-cold binding buffer. Filterplates were subsequently dried at 50° C. for 1-2 hrs. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Binding Data: In one embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has substantially no activity ata κ-opioid receptor. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a Ki (nM) of about 20,000 orless, or about 10,000 or less, or about 5000 or less, or about 500 orless, or about 300 or less, or about 100 or less, or about 50 or less,or about 20 or less, or about 15 or less, or about 10 or less.

5.26 Example 26 In vitro Kappa-Opioid Receptor Functional Assays

κ-Opioid Receptor Functional Assay Procedures: Functional [³⁵S]GTPγSbinding assays were conducted as follows. Kappa opioid receptor membranesolution was prepared by sequentially adding final concentrations of0.026 μg/μL kappa membrane protein (in-house), 10 μg/mL saponin, 3 μMGDP and 0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂,20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (1901L/well) was transferred to 96-shallow well polypropylene platescontaining 10 μL of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at a temperature of about 25°C. with shaking. Reactions were terminated by rapid filtration onto96-well Unifilter GF/B filter plates (Packard) using a 96-well tissueharvester (Packard) and followed by three filtration washes with 200 μLice-cold binding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filterplates were subsequently dried at 50° C. for 2-3 hrs. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

κ-Opioid Receptor Functional Data: κ GTP EC₅₀ is the concentration of acompound providing 50% of the maximal response for the compound at aκ-opioid receptor. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a κ GTP EC₅₀ (nM) of about20,000 or less, or about 10,000 or less, or about 5000 or less, or about2000 or less, or about 1500 or less, or about 800 or less, or about 500or less, or about 300 or less, or about 100 or less, or about 50 orless, or about 10 or less.

κ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by U69,593. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a κ GTP Emax (%) of about 10%or greater, or about 15% or greater, or about 30% or greater, or about40% or greater, or about 45% or greater, or about 75% or greater, orabout 90% or greater, or about 100% or greater. In other embodiments, aSubstituted Benzimidazole-Type Piperidine Compound has a κ GTP Emax (%)of about 10% or less, or about 5% or less, or about 2% or less.

5.27 Example 27 In vitro Delta-opioid Receptor Binding Assays

δ-Opioid Receptor Binding Assay Procedures: Radioliganddose-displacement assays used 0.2 nM [³H]-Naltrindole (NEN; 33.0Ci/mmole) with 10-20 μg membrane protein (recombinant delta opioidreceptor expressed in CHO-K1 cells; Perkin Elmer) in a final volume of500 μL binding buffer (5 mM MgCl₂, 5% DMSO, 50 mM Trizma base, pH 7.4).Non-specific binding was determined in the presence of 25 μM unlabelednaloxone. All reactions were performed in 96-deep well polypropyleneplates for 1 h at a temperature of about 25° C. Binding reactions weredetermined by rapid filtration onto 96-well Unifilter GF/C filter plates(Packard) presoaked in 0.5% polyethylenimine (Sigma-Aldrich). Harvestingwas performed using a 96-well tissue harvester (Packard) followed byfive filtration washes with 500 μL ice-cold binding buffer. Filterplates were subsequently dried at 50° C. for 1-2 hrs. Fifty μL/wellscintillation cocktail (MicroScint20, Packard) was added and plates werecounted in a Packard Top-Count for 1 min/well.

δ-Opioid Receptor Binding Data: In one embodiment, a SubstitutedBenzimidazole-Type Piperidine Compound has substantially no activity ata δ-opioid receptor. In certain embodiments, a SubstitutedBenzimidazole-Type Piperidine Compound has a Ki (nM) of about 20,000 orless, or about 10,000 or less, or about 7500 or less, or about 6500 orless, or about 5000 or less, or about 3000 or less, or about 2500 orless, or about 1000 or less, or about 500 or less, or about 350 or less,or about 250 or less, or about 100 or less, or about 10 or less.

5.28 Example 28 In vitro Delta-Opioid Receptor Functional Assays

δ-Opioid Receptor Functional Assay Procedures: Functional [³⁵S]GTPγSbinding assays were conducted as follows using membranes expressinghuman δ-opioid receptors. Delta opioid receptor membrane solution wasprepared by sequentially adding final concentrations of 0.026 μg/μLdelta membrane protein (Perkin Elmer), 10 μg/mL saponin, 3 μM GDP and0.20 nM [³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mMHEPES, pH 7.4) on ice. The prepared membrane solution (190 μL/well) wastransferred to 96-shallow well polypropylene plates containing 10 μL of20× concentrated stock solutions of agonist prepared in DMSO. Plateswere incubated for 30 min at a temperature of about 25° C. with shaking.Reactions were terminated by rapid filtration onto 96-well UnifilterGF/B filter plates (Packard) using a 96-well tissue harvester (Packard)and followed by three filtration washes with 200 μL ice-cold bindingbuffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates weresubsequently dried at 50° C. for 1-2 hrs. Fifty μL/well scintillationcocktail (MicroScint20, Packard) was added and plates were counted in aPackard Top-count for 1 min/well.

δ-Opioid Receptor Functional Data: δ GTP EC₅₀ is the concentration of acompound providing 50% of the maximal response for the compound at a δreceptor. In certain embodiments, a Substituted Benzimidazole-TypePiperidine Compound has a δ GTP EC₅₀ (nM) of about 20,000 or less, orabout 10,000 or less, or about 100 or less, or about 1000 or less, orabout 90 or less, or about 50 or less, or about 25 or less, or about 10or less.

δ GTP Emax (%) is the maximal effect elicited by a compound relative tothe effect elicited by met-enkephalin. In certain embodiments, aSubstituted Benzimidazole-Type Piperidine Compound has a δ GTP Emax (%)of about 10% or greater, or about 30% or greater, or about 50% orgreater, or about 75% or greater, or about 90% or greater, or about 100%or greater, or about 110% or greater. In other embodiments, aSubstituted Benzimidazole-Type Piperidine Compound has a δ GTP Emax (%)of about 10% or less, or about 5% or less, or about 2% or less.

5.29 Example 29 Efficacy of Receptor Binding and Activity Response

The following Tables provide, for several Substituted Benzimidazole-TypePiperidine Compounds and certain other compounds of interest, results onthe efficacy of binding and activity response to the ORL-1 receptor, themu-opioid receptor, the kappa-opioid receptor, and/or the delta-opioidreceptor and CYP2D6 response.

In Table 18, binding efficacy to the ORL-1 receptor was determined bythe procedure in Example 21. Binding efficacy to the mu-opioid receptorwas determined by the procedure in Example 23. Binding efficacy to thekappa-opioid receptor was determined by the procedure in Example 25.Binding efficacy to the delta-opioid receptor was determined by theprocedure in Example 27.

In Table 19, activity response to the ORL-1 receptor was determined bythe procedure in Example 22. Activity response to the mu-opioid receptorwas determined by the procedure in Example 24. Activity response to thekappa-opioid receptor was determined by the procedure in Example 26.Activity response to the delta-opioid receptor can be determined by theprocedure in Example 28.

TABLE 18 Efficacy of Receptor Binding of Substituted Benzimidazole-TypePiperidine Compounds and Certain Other Compounds of Interest K_(i)[Average ± Std Deviation] (nM) Opioid Receptor Ref. No. Compound ORL-1Mu Kappa Delta B56c(i)

2068 ± 98 — — — B56c(ii)

220 ± 24 >20,000 353 ± 39 >20,000 E30c(ii)

37.9 ± 4.1 — — — E32c(ii)

690 ± 84 — — — E56c(ii)

583 ± 40 — — — H4d

4.73 ± 0.07 — — — H6d

8.9 ± 0.3 — — — H27(b)

1.9 ± 0.4 — — — H30b(i)

18.2 ± 5.7 3560 ± 790 150 ± 44 16,200 H30b(ii)

9.0 ± 2.2 1112 ± 297 65.2 ± 14.1 5275 ± 1863 H30d(ii)

18.6 ± 2.4 — — — H32b(ii)

96.9 ± 13.9 5540 ± 1640 828 ± 98 >20,000 H32d(ii)

86 ± 20 — — — H36b(i)

19.0 ± 1.3 1670 ± 360 123 ± 19 >20,000 H56b(i)

45.5 ± 3.6 4640 ± 1150 108 ± 8 6790 ± 1270 H56b(ii)

55 ± 11 11,320 ± 3,780 16.3 ± 5.3 >20,000 H56d(ii)

43.4 ± 10.7 7450 ± 1460 700 ± 180 >20,000 H58d(ii)

86 ± 8 >20,000 254 ± 57 >20,000 H62d(ii)

15.7 ± 2.4 — — — O85d

21.7 ± 3.2 11,770 41.3 ± 16.5 12,140 ZA07

42.7 ± 5.6 — — — ZA08

92 ± 16 — — — ZA09

14.2 ± 1.2 — — — ZA10

23.5 ± 3.0 >20,000 822 ± 260 >20,000 ZA11

182 ± 25 — — — ZA12

117 ± 15 — — — ZA14

505 ± 29 — — — ZA16

3250 ± 303 — — — ZA18

251 ± 10 — — — ZA20

1250 ± 97 — — — ZA23

27.7 ± 0.4 — — — ZA25

66 ± 14 >20,000 6800 ± 710 10,900 ZA26

17.5 ± 2.7 511 ± 73 59 ± 21 1616 ± 213 ZA27

36.7 ± 2.0 339 ± 21 33.7 ± 3.2 10,260 ± 390 ZA28

22.4 ± 2.6 2473 ± 733 26.2 ± 8.0 5655 ± 677 ZA29

37.1 ± 6.6 2771 ± 854 594 ± 160 — ZA31

65.0 ± 11.1 — — — ZA33

59.1 ± 7.3 1183 ± 173 265 ± 21 13,600 ± 1,960 ZA35

2.68 ± 0.12 1577 ± 204 246 ± 77 >20,000 ZA37

102 ± 19 1497 ± 228 1543 ± 92 3960 ± 710 ZA38

780 ± 165 — — — ZA39

5.1 ± 0.7 — 566 ± 71 — ZA40

2.0 ± 0.63 — — — ZA41

1.15 ± 0.23 — — — ZA42

0.92 ± 0.10 — — — ZA43

14.9 ± 0.7 1837 ± 476 43.7 ± 11.1 >20,000 ZA44

167.1 ± 2.5 — — — ZA45

120 ± 14 — — — ZA46

17.0 ± 2.3 4006 ± 796 344 ± 63 >20,000 ZA47

117 ± 38 — — — ZA48

36.0 ± 4.9 4497 ± 1124 614 ± 92 >20,000 ZA49

11.5 ± 1.4 — — — ZA50

6.14 ± 0.73 1879 ± 120 58.3 ± 3.0 >20,000 ZA51

47.9 ± 4.6 — — — ZA52

15.8 ± 1.6 3007 ± 242 30.4 ± 4.4 >20,000 ZA53

0.80 ± 0.26 — — — ZA54

49 ± 15 2846 ± 629 254 ± 61 >20,000 ZA55

5.4 ± 0.8 1914 ± 292 31.3 ± 4.9 >20,000 ZA56

2.05 ± 0.47 1669 ± 612 50.1 ± 5.9 >20,000 ZA57

8.5 ± 1.1 — — — ZA58

19.9 ± 3.9 4335 ± 546 444 ± 113 >20,000 ZA59

29.5 ± 2.2 3003 ± 112 169 ± 13 >20,000 ZA60

4.5 ± 0.2 — 114.8 ± 2.9 — ZA61

3.8 ± 0.7 — 130 ± 26 — ZA62

47.2 ± 3.7 — — — ZA63

4.11 ± 0.45 — — — ZA64

21.6 ± 4.2 — — — ZA65

40 ± 8 — — — ZA66

7.1 ± 1.2 — — — ZA67

4.2 ± 0.7 — — — ZA68

6.0 ± 1.1 520 ± 46 89.6 ± 9.1 >20,000 ZA69

4.9 ± 0.9 529 ± 34 51 ± 14 6160 ± 1450 ZA70

6.7 ± 1.0 952 ± 67 79 ± 6 4170 ± 495 ZA71

20.8 ± 4.2 — — —

TABLE 19 Activity Response of Substituted Benzimidazole-Type PiperidineCompounds GTPγS (EC₅₀: nM, Emax: %) [mean ± SEM] Opioid Receptor ORL-1EC₅₀ Ref. No. EC₅₀ E_(max) Mu Kappa B56c(ii) 1034 ± 30  31.3 ± 2.7 — —E30C(ii) 336 ± 27 125.3 ± 4.3  — — H4d  37.7 ± 11.3 102 ± 1  — — H6d38.9 ± 7.0 101.7 ± 3.4  — — H27(b) 23.2 ± 2.2 98.3 ± 2.0 — — H30b(i)16.2 ± 2.2 55.7 ± 3.7 — — H30b(ii) 39.6 ± 6.3 41 ± 1 — >20,000 H30d(ii) 65 ± 28 85.3 ± 4.3 — — H32b(ii) 139 ± 23 49.7 ± 9.3 — >20,000 H32d(ii)160 ± 35 90 ± 3 — — H36b(i) 38 ± 8 35.3 ± 1.5 — >20,000 H56b(i) 121 ± 1740.3 ± 2.2 — >20,000 H56b(ii) 104 ± 21 38.5 ± 2.1 — 1533 ± 147 H56d(ii) 95 ± 20 66.7 ± 5.5 — >20,000 H58d(ii)  78 ± 15 41.7 ± 3.8 — >20,000H62d(ii)  6.2 ± 0.8 18.7 ± 3.2 — — O85d  67 ± 18 60 ± 1 — >20,000 ZA07140 ± 17  106 ± 3.8 — — ZA08 253 ± 20 104.3 ± 5.9  — — ZA09 37.0 ± 6.385.0 ± 2.6 — — ZA10 138.7 ± 8.3  75.67 ± 0.88 — >20,000 ZA11 502 ± 9923.0 ± 0.6 — — ZA12 390 ± 34 24.3 ± 0.9 — — ZA23 >20,000 — — — ZA25 136± 15 36.0 ± 3.2 — — ZA26  46.7 ± 16.3 106.3 ± 8.8  3813 ± 821  721 ± 97ZA27  91.4 ± 13.3 90.7 ± 3.5 2764 ± 1459 824 ± 94 ZA28  70.8 ± 11.2107.3 ± 4.2  — 1011 ± 112 ZA29 124 ± 21 66.0 ± 4.7 — 5418 ± 820 ZA3164.8 ± 2.5 21.67 ± 0.33 — — ZA33 219.9 ± 8.6  120.7 ± 6.7  — >20,000ZA35 17.5 ± 1.5 33.0 ± 1.3 — >20,000 ZA37 84.2 ± 2.2 34.7 ± 1.5 — —ZA39 >20,000 — — >20,000 ZA40  5.8 ± 0.5 22.3 ± 1.3 — — ZA41  3.0 ± 1.310.3 ± 0.9 — — ZA42 >20,000 — — — ZA43 59.3 ± 3.9 58.3 ± 2.3 — >20,000ZA44  355 ± 114 48.7 ± 1.8 — — ZA45 22.8 ± 3.2 15 ± 1 — — ZA46 43.1 ±9.3 51.7 ± 1.7 — >20,000 ZA47  82 ± 18 22.8 ± 0.8 — — ZA48 62.5 ± 4.663.3 ± 3.8 — >20,000 ZA49 12.5 ± 4.0 16.3 ± 0.3 — — ZA50  8.9 ± 1.8 43 ±3 — >20,000 ZA51  40 ± 15 11 ± 1 — — ZA52 28.4 ± 7.4 31.7 ± 3.3— >20,000 ZA53  3.6 ± 0.8 14.3 ± 1.0 — — ZA54 72.5 ± 9.3 40.7 ± 0.9— >20,000 ZA55 17.0 ± 1.2 61.3 ± 1.5 — >20,000 ZA56  4.7 ± 0.4 56.0 ±2.1 — >20,000 ZA57 26.9 ± 2.5 23.3 ± 0.9 — — ZA58 103.9 ± 2.3  66 ± 2— >20,000 ZA59 101 ± 15 40.3 ± 0.7 — >20,000 ZA60 12.6 ± 1.5 53.7 ± 4.2— — ZA61  5.61 ± 0.25 28.8 ± 2.5 — — ZA62 38.4 ± 8.3 17.3 ± 0.3 — —ZA63 >20,000 — — — ZA64  8 ± 3  7.0 ± 0.7 — — ZA65 71.7 ± 5.2 21 ± 1 — —ZA66 16.6 ± 1.0 22.7 ± 1.2 — — ZA67 14.3 ± 3.7 23.3 ± 0.9 — — ZA68 28.4± 2.3 26 ± 2 564 ± 189 >20,000 ZA69 10.4 ± 1.1 31.7 ± 0.9 466 ±165 >20,000 ZA70 22.6 ± 5.2 29.3 ± 0.9 4750 ± 1270 >20,000 ZA71 >20,000— — —

5.30 Example 30 In Vivo Assays for Prevention or Treatment of Pain

Test Animals Each experiment uses rats weighing between 200-260 g at thestart of the experiment. The rats are group-housed and have free accessto food and water at all times, except prior to oral administration of aSubstituted Benzimidazole-Type Piperidine Compound when food is removedfor 16 hrs before dosing. A control group acts as a comparison to ratstreated with a Substituted Benzimidazole-Type Piperidine Compound. Thecontrol group is administered the carrier for the SubstitutedBenzimidazole-Type Piperidine Compound. The volume of carrieradministered to the control group is the same as the volume of carrierand Substituted Benzimidazole-Type Piperidine Compound administered tothe test group.

Acute Pain: To assess the actions of a Substituted Benzimidazole-TypePiperidine Compound for the treatment or prevention of acute pain, therat tail flick test can be used. Rats are gently restrained by hand andthe tail exposed to a focused beam of radiant heat at a point 5 cm fromthe tip using a tail flick unit (Model 7360, commercially available fromUgo Basile of Italy). Tail flick latencies are defined as the intervalbetween the onset of the thermal stimulus and the flick of the tail.Animals not responding within 20 seconds are removed from the tail flickunit and assigned a withdrawal latency of 20 seconds. Tail flicklatencies are measured immediately before (pre-treatment) and 1, 3, and5 hrs following administration of a Substituted Benzimidazole-TypePiperidine Compound. Data are expressed as tail flick latency(s) and thepercentage of the maximal possible effect (% MPE), i.e., 20 seconds, iscalculated as follows:

${\% \mspace{14mu} {MPE}} = {\frac{\lbrack {( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} ) - ( {{pre}\text{-}{administration}\mspace{14mu} {latency}} )} \rbrack}{( {20\mspace{14mu} s\mspace{14mu} {pre}\text{-}{administration}\mspace{14mu} {latency}} )} \times 100}$

The rat tail flick test is described in D'Amour et al., “A Method forDetermining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther. 72:74-79(1941).

Inflammatory Pain: To assess the actions of a SubstitutedBenzimidazole-Type Piperidine Compound for the treatment or preventionof inflammatory pain, the Freund's complete adjuvant (“FCA”) model ofinflammatory pain can be used. FCA-induced inflammation of the rat hindpaw is associated with the development of persistent inflammatorymechanical hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., “Involvement of capsaicin-sensitive neurons in hyperalgesia andenhanced opioid antinociception in inflammation,” Naunyn-Schmiedeberg'sArch. Pharmacol. 342:666-670 (1990)). The left hind paw of each animalis administered a 50 μL intraplantar injection of 50% FCA. 24 hr postinjection, the animal is assessed for response to noxious mechanicalstimuli by determining the PWT, as described below. Rats are thenadministered a single injection of 1, 3, 10 or 30 mg/kg of either aSubstituted Benzimidazole-Type Piperidine Compound; 30 mg/kg of acontrol selected from Celebrex, indomethacin, and naproxen; or carrier.Responses to noxious mechanical stimuli are then determined 1, 3, 5 and24 hrs post administration. Percentage reversal of hyperalgesia for eachanimal is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\lbrack {( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} ) - ( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} )} \rbrack}{\lbrack {( {{baseline}\mspace{14mu} {PWT}} ) - ( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} )} \rbrack} \times 100}$

Neuropathic Pain To assess the actions of a SubstitutedBenzimidazole-Type Piperidine Compound for the treatment or preventionof neuropathic pain, either the Seltzer model or the Chung model can beused.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the male, 6-7 week old Jcl:SD rat is shaved. Thesciatic nerve is exposed at high thigh level through a small incisionand is carefully cleared of surrounding connective tissues at a sitenear the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a ⅜ curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. The wound area is then dusted with antibiotic powder. Shamtreatment involves an identical surgical procedure except that thesciatic nerve is not manipulated or ligated.

Following surgery, animals are weighed and placed on a warm pad untilthey recovered from anesthesia. Animals are then returned to their homecages until behavioral testing began. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT for the rearpaw of the animal, as described below, prior to surgery (baseline), thenimmediately prior to and 1, 3, and 5 hrs after oral drug-in-vehicleadministration (for day 1). Thus, the 24 hr time point is the start ofthe next day when drug-in-vehicle is again orally administered (24 hrsafter the prior administration). On days 4 and 7, PWT response isdetermined 1, 3, and 5 hrs thereafter. Percentage reversal ofneuropathic hyperalgesia at each of the specified times afteradministration is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\lbrack {( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} ) - ( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} )} \rbrack}{\lbrack {( {{baseline}\mspace{14mu} {PWT}} ) - ( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} )} \rbrack} \times 100}$

Additionally, 10 mg/kg of pregabalin (Kemprotec, Ltd., Middlesbrough,UK), an anticonvulsant accepted for relief of particular neuropathicpain, in vehicle and the vehicle alone (0.5% weight/volumemethylcellulose (400 cP, Wako Pure Chemical Industries, Ltd.)/aqueoussolution) are orally administered as controls. Eight rats that underwentpartial ligation of the left sciatic nerve are used for each treatmentgroup except for pregabalin, where six rats are treated. Dunnett's testis conducted for the % reversal; values with p<0.05 are considered to bestatistically significant. Additionally, as a control the rats undergosham surgery in which an identical surgical procedure is followed withregard to the right thigh but the sciatic nerve is neither manipulatednor ligated.

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia, a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hrs after being administered a SubstitutedBenzimidazole-Type Piperidine Compound for the left rear paw of theanimal. The animal can also be assessed for response to noxious thermalstimuli or for tactile allodynia, as described below. The Chung modelfor neuropathic pain is described in Kim, “An Experimental Model forPeripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in theRat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia: The paw pressure assay can be used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus are determined using an analgesymeter (Model37215, commercially available from Ugo Basile of Italy) as described inStein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. Behavior 31:451-455 (1988). The maximumweight that can be applied to the hind paw is set at 250 g and the endpoint is taken as complete withdrawal of the paw. PWT is determined oncefor each rat at each time point and either only the affected(ipsilateral) paw is tested, or both the ipsilateral and contralateral(non-injured) paw are tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by Hargreaves etal., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Either onlythe affected (ipsilateral) paw is tested, or both the ipsilateral andcontralateral (non-injured) paw are tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats areplaced in clear, plexiglass compartments with a wire mesh floor andallowed to habituate for a period of at least 15 min. After habituation,a series of von Frey monofilaments are presented to the plantar surfaceof the left (operated) foot of each rat. The series of von Freymonofilaments consists of six monofilaments of increasing diameter, withthe smallest diameter fiber presented first. Five trials are conductedwith each filament with each trial separated by approximately 2 minutes.Each presentation lasts for a period of 4-8 seconds or until anociceptive withdrawal behavior is observed. Flinching, paw withdrawalor licking of the paw are considered nociceptive behavioral responses.

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims. A number of referenceshave been cited, the entire disclosures of which are incorporated hereinby reference for all purposes.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof wherein: theQ_(a) ring is fused benzo or fused (5- or 6-membered)heteroaryl; each R²is independently selected from: (a) -halo, —CN, —NO₂, —OT³, —C(═O)T³,—C(═O)OT³, —C(═O)N(T¹)(T²), —S(═O)₂OT³, —S(═O)T³, —S(═O)₂T³,—O—S(═O)₂T³, —S(═O)₂N(T¹)(T²), —N(T¹)(T²), —N(T³)C(═O)T³,—N(T³)C(═O)N(T¹)(T²), —N(T³)S(═O)T³, —N(T³)S(═O)₂T³, —N(T³)C(═O)OT³, and—N(T³)S(═O)₂N(T¹)(T²); and (b) —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl,—(C₆-C₁₀)bicycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₇-C₁₀)bicycloalkenyl,and -(5- or 6-membered)heterocycle, each of which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁸ groups; and(c)-phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl, each ofwhich is unsubstituted or substituted with 1, 2, or 3 independentlyselected R⁷ groups; each dashed line denotes the presence or absence ofa bond, provided that: (a) one dashed line must denote the presence of abond; (b) when one dashed line denotes the presence of a bond then theother dashed line denotes the absence of a bond; (c) when the dashedline within the 5-membered, nitrogen-containing ring that is fused tothe Q_(a) ring is present, then R³ is absent; and (d) when the dashedline within the 5-membered, nitrogen-containing ring that is fused tothe Q_(a) ring is absent, then R³ is present; R³, when present, is: (a)—H; or (b) —(C₁-C₄)alkyl which is unsubstituted or substituted with 1,2, or 3 groups independently selected from —OH, —(C₁-C₄)alkoxy, —N(R⁶)₂,—C(═O)OR⁹, and —C(═O)N(R⁶)₂; or (c) —(C₃-C₇)cycloalkyl which isunsubstituted or substituted with 1, 2, or 3 groups independentlyselected from —OH, —(C₁-C₄)alkyl, —(C₁-C₄)alkoxy, —N(R⁶)₂, —C(═O)OR⁹,and —C(═O)N(R⁶)₂;

is a single bond, a double bond, ═CH—, —CH₂—, ═N—, —NH—, —O—,═CH—(C₁-C₃)alkylene-, —CH₂—(C₁-C₃)alkylene-, ═N—(C₁-C₃)alkylene-,—NH—(C₁-C₃)alkylene-, —O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-,—CH₂—(C₂-C₃)alkenylene-, ═N—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-,—O—(C₂-C₃)alkenylene-, ═CH—(C₁-C₃)alkylene-N(R¹¹)—,—CH₂—(C₁-C₃)alkylene-N(R¹¹)—, ═N—(C₁-C₃)alkylene-N(R¹¹)—,—NH—(C₁-C₃)alkylene-N(R¹¹)—, —O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—,—CH═N—, —CH₂—N(R¹¹)—, ═CH—O—, —CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or—CH₂—O—(C₁-C₃)alkylene-; U is: (a) —R¹⁵; or (b)

 wherein when

is a single bond or a double bond the Q_(x) ring is a -(4-, 5-, 6-, or7-membered)heterocycle containing one or two ring heteroatoms selectedfrom N,N(R⁴), O, and S provided that at least one ring heteroatom is Nor N(R⁴) and wherein either U¹ is N and U² is a bond or UI is C or CHand U² is N or N(R⁴), provided that; (1) when

is a double bond and the Q_(x) ring is present, U¹ is C; and (2) when

is ═CH—, —CH₂—, ═CH—(C₁-C₃)alkylene-, or —CH₂—(C₁-C₃)alkylene- and theQ_(x) ring is present, the Q_(x) ring is a (6-membered)heterocycleselected from:

 and (3) when

is ═N—, —NH—, —O—, ═N—(C₁-C₃)alkylene-, —NH—(C₁-C₃)alkylene-,—O—(C₁-C₃)alkylene-, ═CH—(C₂-C₃)alkenylene-, —CH₂—(C₂-C₃)alkenylene-,═N—(C₂-C₃)alkenylene-, —NH—(C₂-C₃)alkenylene-, —O—(C₂-C₃)alkenylene-,═CH—(C₁-C₃)alkylene-N(R¹¹)—, —CH₂—(C₁-C₃)alkylene-N(R¹¹)—,═N—(C₁-C₃)alkylene-N(R¹¹)—, —NH—(C₁-C₃)alkylene-N(R¹¹)—,—O—(C₁-C₃)alkylene-N(R¹¹)—, ═CH—N(R¹¹)—, —CH═N—, —CH₂—N(R¹¹)—, ═CH—O—,—CH₂—O—, ═CH—O—(C₁-C₃)alkylene-, or —CH₂—O—(C₁-C₃)alkylene-, then theQ_(x) ring is absent; each R⁴, when present, is independently selectedfrom: (a) —H; and (b) —X, —(C₁-C₆)alkyl-X, -(5- or6-membered)heterocycle-X, or -(5- or6-membered)heterocycle-(C₁-C₆)alkyl-X; and (c) —(CH₂)_(d)—C(═Y)CN,—(CH₂)_(d)—C(═Y)X, —(CH₂)_(d)—C(═Y)T³, —(CH₂)_(d)—C(═Y)YX,—(CH₂)_(d)—C(═Y)YT³, —(CH₂)_(d)—C(═Y)N(T¹)(T²), —(CH₂)_(d)—C(═Y)N(R⁹)CN,—(CH₂)_(d)—C(═Y)N(R⁹)X, —(CH₂)_(d)—C(═Y)N(R⁹)YH,—(CH₂)_(d)—C(═Y)N(R⁹)YX, —(CH₂)_(d)—C(═Y)N(R⁹)YCH₂X,—(CH₂)_(d)—C(═Y)N(R⁹)YCH₂CH₂X, or —(CH₂)_(d)—C(═Y)N(R⁹)S(═O)₂T³; and (d)—[CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—O]_(b)—R¹⁶, —[CH₂—CH₂—O]_(b)—R¹⁶,—[CH(CH₃)—CH₂—O]_(b)—R¹⁶, —[CH₂—CH(CH₃)—O]_(b)—R¹⁶,—[CH₂—CH₂—CH₂—O]_(b)—R¹⁶, —[CH(CH₃)—CH₂—CH₂—O]_(b)—R¹⁶,—[CH₂—CH(CH₃)—CH₂—O]_(b)—R¹⁶, or —[CH₂—CH₂—CH(CH₃)—O]_(b)—R¹⁶; X isselected from: (a) —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₁-C₆)alkoxy, —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, and -(5- or6-membered)heterocycle, each of which is unsubstituted or substitutedwith 1, 2, or 3 independently selected R⁸ groups; and (b)-phenyl and-(5- or 6-membered)heteroaryl, each of which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁷ groups; each Y isindependently O or S; each R¹⁶ is independently H or CH₃; s is aninteger selected from 0, 1, and 2; when s is 1, R¹⁰ is —F, —CH₃,—CH₂CH₃, —(CH₂)_(d)—C(═Y)YT³, or —(CH₂)_(d)—C(═Y)N(T¹)(T²), and when sis 2, the R¹⁰ groups together are gem-dimethyl, gem-difluoro, ═O, or ═S;A and B are independently selected from: (a) —H; and (b) —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, and —(C₁-C₆)alkoxy, each of which is unsubstituted orsubstituted with 1 or 2 substituents independently selected from —OH,—S(═O)₂NH₂, —C(═O)OT³, —C(═O)N(R⁶)₂, and —N(R⁶)C(═O)R⁹, or 1, 2, or 3independently selected -halo; or (c) A-B can together form a(C₂-C₆)bridge, which is unsubstituted or substituted with 1, 2, 3, 4, 5,6, 7, or 8 substituents independently selected from —OH, —(C₁-C₄)alkyl,-halo, and —C(halo)₃, and which bridge optionally contains —HC═CH— or—O— within the (C₂-C₆)bridge; wherein the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring can be in theendo- or exo-configuration with respect to the A-B bridge; wherein the5-membered, nitrogen-containing ring that is fused to the Q_(a) ring canbe in the endo- or exo-configuration with respect to the A-B bridge; Zis —[(C₁-C₁₀)alkyl optionally substituted by R¹³]_(h)—, wherein h is 0or 1; or —[(C₂-C₁₀)alkenyl optionally substituted by R¹³]—, or—[(C₁-C₁₀)alkyl-NR⁶C(═Y)]—; R¹ is selected from: (a) —H, -halo, —CN,—OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂, —S(═O)₂NH₂, —C(═O)OV¹,and —C(═O)CN; and (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl,—(C₂-C₁₀)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,—(C₆-C₁₄)bicycloalkyl, —(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₇-C₁₄)bicycloalkenyl, —(C₈-C₂₀)tricycloalkenyl, and -(3- to7-membered)heterocycle, each of which is unsubstituted or substitutedwith 1, 2, 3, or 4 independently selected R⁸ groups; and (c)

 and (d) -phenyl, -naphthalenyl, —(C₁₄)aryl, and -(5- to10-membered)heteroaryl, each of which is unsubstituted or substitutedwith 1, 2, 3, or 4 independently selected R⁷ groups; each R⁵ isindependently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, ═O, ═S, -halo, —N₃, —NO₂, —CH═N(R⁹),—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)OR⁹,—OC(═O)R⁹, —OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹; each R⁶ is independently—H, —(C₁-C₆)alkyl, or —(C₃-C₇)cycloalkyl, or two R⁶ groups attached tothe same nitrogen atom can together form a -(5- to8-membered)heterocyclic ring, wherein the number of atoms in the ringincludes the nitrogen atom, and in which one of the -(5- to8-membered)heterocyclic ring carbon atoms is optionally replaced by O,S, or N(T³); each R⁷ is independently —(C₁-C₄)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,-halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂, —N(R⁹)OH, —N(R⁹)S(═O)R¹²,—N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹², —N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹²,—C(═O)R⁹, —C(═O)N(T¹)(T²), —C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²),—OC(═O)OR⁹, —S(═O)R⁹, or —S(═O)₂R⁹; each R⁸ is independently—(C₁-C₄)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, -(5- or6-membered)heteroaryl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —SR⁹, —C(halo)₃, —CH(halo)₂,—CH₂(halo), —CN, ═O, ═S, ═N(R⁹), -halo, —N₃, —NO₂, —CH═N(R⁹), —N(R⁹)₂,—N(R⁹)OR⁹, —N(R⁹)S(═O)R¹², —N(R⁹)S(═O)₂R¹², —N(R⁹)C(═O)R¹²,—N(R⁹)C(═O)N(T¹)(T²), —N(R⁹)C(═O)OR¹², —C(═O)R⁹, —C(═O)N(T¹)(T²),—C(═O)OR⁹, —OC(═O)R⁹, —OC(═O)N(T¹)(T²), —OC(═O)OR⁹, —S(═O)R⁹, or—S(═O)₂R⁹; each R⁹ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,-benzyl, -(3- to 7-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or—CH₂(halo); R¹¹ is —H, —CN, or —C(═O)N(R⁶)₂ or R¹¹ is —(C₁-C₄)alkylwhich is unsubstituted or substituted with —OH, —(C₁-C₄)alkoxy, or—N(R⁶)₂; each R¹² is independently —H or —(C₁-C₄)alkyl; R¹³ is selectedfrom: (a) -halo, —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂,—S(═O)₂NH₂, —C(═O)OV¹, and —C(═O)CN; and (b) —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —O(C₁-C₆)alkyl, —(C₃-C₇)cycloalkoxy,—(C₅-C₁₀)cycloalkenyl, and -(3- to 7-membered)heterocycle, each of whichis unsubstituted or substituted with 1, 2, 3, or 4 independentlyselected R⁸ groups; and (c)

 and (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁷groups; R¹⁵, when present, is selected from: (a) —H; and (b)—(C₁-C₄)alkyl and —O—(C₁-C₄)alkyl, each of which is unsubstituted orsubstituted with 1, 2, 3, or 4 independently selected R⁸ groups; (c)provided that when

is a single bond, a double bond, or —O—, R¹⁵ is not —H; each T¹ and T²is independently —H or —(C₁-C₁₀)alkyl which is unsubstituted orsubstituted with 1, 2, or 3 independently selected R⁵ groups and,optionally, in which any —(C₁-C₁₀)alkyl carbon atom except the carbonatom bonded directly to the atom to which T¹ or T² is attached isindependently replaced by O, S, or N(R⁶), or T¹ and T² can together forma -(5- to 8-membered)heterocyclic ring wherein the number of atoms inthe ring includes the nitrogen atom to which T¹ and T² are bonded, said-(5- to 8-membered)heterocyclic ring is unsubstituted or substitutedwith 1, 2, or 3 independently selected R⁵ groups and, optionally, any 1or 2 carbon atoms in said -(5- to 8-membered)heterocyclic ring isindependently replaced by O, S, or N(R⁶); each T³ is independently —H or—(C₁-C₁₀)alkyl which is unsubstituted or substituted with 1, 2, or 3independently selected R⁵ groups and, optionally, in which any—(C₁-C₁₀)alkyl carbon atom except the carbon atom bonded directly to theatom to which T³ is attached is independently replaced by O, S, orN(R¹²); each V¹ is independently —H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,-phenyl, or -benzyl; a is an integer selected from 0, 1, and 2; each bis, independently, an integer selected from 1, 2, 3, 4, 5, and 6; each dis, independently, an integer selected from 0, 1, 2, and 3; m is aninteger selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; n is aninteger selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9; e and f are eachan integer independently selected from 0, 1, 2, 3, 4, and 5 providedthat 2≦(e+f)≦5; each p is an integer independently selected from 0, 1,2, 3, and 4; and each halo is independently —F, —Cl, —Br, or —I.
 2. Thecompound of claim 1 which is a compound of Formula (IA):

or a pharmaceutically acceptable salt or solvate thereof wherein: t isan integer selected from 0, 1, 2, and 3; when t is 0, the Q_(x) ring isa -(4-, 5-, 6-, or 7-membered)heterocycle containing one or two ringheteroatoms selected from N,N(R⁴), O, and S provided that at least onering heteroatom is N or N(R⁴) and provided that when the dashed lineconnecting the Q_(x) ring to the 5-membered, nitrogen-containing ringthat is fused to the Q_(a) ring is present, U¹ is C or CH, and when t is1, 2, or 3 the Q_(x) ring is a (6-membered)heterocycle selected from:


3. The compound of claim 1 which is a compound of Formula (IB)

or a pharmaceutically acceptable salt or solvate thereof.
 4. Thecompound of claim 1 or a pharmaceutically acceptable salt or solvatethereof, wherein Q_(a) is benzo, pyridino, pyrimidino, pyrazino, orpyridazino wherein the 2- and 3-positions of the pyridino are fused tothe 5-membered, nitrogen-containing ring.
 5. The compound of claim 1 ora pharmaceutically acceptable salt or solvate thereof, wherein Q_(a) isbenzo.
 6. The compound of claim 5 or a pharmaceutically acceptable saltor solvate thereof, wherein a is
 0. 7. The compound of claim 2 or apharmaceutically acceptable salt or solvate thereof, wherein: Q_(a) isbenzo; a is 0; A-B together form a (C₂-C₆)bridge, which is unsubstitutedor substituted with 1, 2, 3, 4, 5, 6, 7 or 8 substituents independentlyselected from —OH, —(C₁-C₄)alkyl, -halo, and —C(halo)₃, and which bridgeoptionally contains —HC═CH— or —O— within the (C₂-C₆)bridge; wherein theA-B bridge can be in the endo- or exo-configuration with respect to the5-membered, nitrogen-containing ring that is fused to the Q_(a) ring; Zis —[(C₁-C₁₀)alkyl]_(h)-, wherein h is 0 or 1; and R¹ is selected from:(a) —CN, —OH, —CH₂OH, —CH₂CH₂OH, —NO₂, —N(R⁶)₂, —S(═O)NH₂, —S(═O)₂NH₂,—C(═O)OV¹, and —C(═O)CN; and (b) —(C₁-C₁₀)alkyl, —O(C₁-C₆)alkyl,—(C₃-C₇)cycloalkoxy, —(C₃-C₁₄)Cycloalkyl, —(C₆-C₁₄)bicycloalkyl,—(C₈-C₂₀)tricycloalkyl, —(C₅-C₁₄)cycloalkenyl, —(C₇-C₁₄)bicycloalkenyl,—(C₈-C₂₀)tricycloalkenyl, and -(3- to 7-membered)heterocycle, each ofwhich is unsubstituted or substituted with 1, 2, 3, or 4 independentlyselected R⁸ groups; and (c)

 and (d) -phenyl and -(5- to 10-membered)heteroaryl, each of which isunsubstituted or substituted with 1, 2, or 3 independently selected R⁷groups.
 8. The compound of claim 7 or a pharmaceutically acceptable saltor solvate thereof, wherein each b is, independently, an integerselected from 2 and
 3. 9. The compound of claim 8 or a pharmaceuticallyacceptable salt or solvate thereof, wherein each b is
 3. 10. Thecompound of claim 7 or a pharmaceutically acceptable salt or solvatethereof, wherein t is 1 and the Q_(x) ring is selected from:


11. The compound of claim 10 or a pharmaceutically acceptable salt orsolvate thereof, wherein the Q_(x) ring is selected from:


12. The compound of claim 11 or a pharmaceutically acceptable salt orsolvate thereof, wherein s is
 0. 13. The compound of claim 7 or apharmaceutically acceptable salt or solvate thereof, wherein t is 1, 2,or 3 and the Q_(x) ring is selected from:


14. The compound of claim 7 or a pharmaceutically acceptable salt orsolvate thereof, wherein t is 0 and the Q_(x) ring is selected from:


15. The compound of claim 14 or a pharmaceutically acceptable salt orsolvate thereof, wherein s is
 0. 16. The compound of claim 2 or apharmaceutically acceptable salt or solvate thereof, wherein the dashedline within the 5-membered, nitrogen-containing ring that is fused tothe Q_(a) ring is present to provide one bond of a double bond.
 17. Thecompound of claim 3 or a pharmaceutically acceptable salt or solvatethereof, wherein the dashed line within the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring is present toprovide one bond of a double bond.
 18. The compound of claim 17 or apharmaceutically acceptable salt or solvate thereof, wherein ═W— is asingle bond, a double bond, —CH₂—, ═N—, —CH═N—, or —NH—.
 19. Thecompound of claim 18 or a pharmaceutically acceptable salt or solvatethereof, wherein R¹⁵ is —OH, —C(═O)OH, —C(═O)OCH₃, —C(═O)OC₂H₅,—C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.
 20. The compound ofclaim 19 or a pharmaceutically acceptable salt or solvate thereof,wherein ═W— is —CH₂—, ═N—, —CH═N—, or —NH— and R¹⁵ is —C(═O)OH,—C(═O)OCH₃, —C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃,—CH₂C(═O)OC₂H₅, —OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃,—OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or—C(═NH)NHOC₂H₅.
 21. The compound of claim 19 or a pharmaceuticallyacceptable salt or solvate thereof, wherein ═W— is —CH₂—, ═N—, —CH═N—,or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OCH₂C(═O)OH, —C(═NH)OC₂H₅, or —C(═NH)NHOCH₃.
 22. Thecompound of claim 19 or a pharmaceutically acceptable salt or solvatethereof, wherein ═W— is —CH₂— or —CH═N— and R¹⁵ is —C(═O)OH, —C(═O)OCH₃,—C(═O)OC₂H₅, —C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅,—OC(═O)CH₃, —OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅,—C(═NH)OCH₃, —C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.
 23. Thecompound of claim 19 or a pharmaceutically acceptable salt or solvatethereof, wherein ═W— is ═N— or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅,—C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.
 24. The compound ofclaim 19 or a pharmaceutically acceptable salt or solvate thereof,wherein ═W— is —CH═N— or —NH— and R¹⁵ is —C(═O)OCH₃, —C(═O)OC₂H₅,—C(═O)NH₂, —CH₂C(═O)OH, —CH₂C(═O)OCH₃, —CH₂C(═O)OC₂H₅, —OC(═O)CH₃,—OC(═O)C₂H₅, —OCH₂C(═O)OH, —OCH₂C(═O)OCH₃, —OCH₂C(═O)OC₂H₅, —C(═NH)OCH₃,—C(═NH)OC₂H₅, —C(═NH)NHOCH₃, or —C(═NH)NHOC₂H₅.
 25. The compound ofclaim 1 which is:

or a pharmaceutically acceptable salt or solvate thereof.
 26. Thecompound of claim 25 which is:

or a pharmaceutically acceptable salt or solvate thereof.
 27. Thecompound of claim 7 or a pharmaceutically acceptable salt or solvatethereof, wherein h is
 1. 28. The compound of claim 27 or apharmaceutically acceptable salt or solvate thereof, wherein Z is—(C₁-C₃)alkyl-optionally substituted by R¹³.
 29. The compound of claim28 or a pharmaceutically acceptable salt or solvate thereof, wherein R¹³is absent.
 30. The compound of claim 29 or a pharmaceutically acceptablesalt or solvate thereof, wherein R¹³ is absent and Z is —CH₂—CH₂—. 31.The compound of claim 30 or a pharmaceutically acceptable salt orsolvate thereof, wherein —Z—R¹ is:

wherein each R^(z) is independently —H, —CH₃, or —CH₂CH₃.
 32. Thecompound of claim 7 or a pharmaceutically acceptable salt or solvatethereof, wherein h is
 0. 33. The compound of claim 32 or apharmaceutically acceptable salt or solvate thereof, wherein A and B areindependently —H or —CH₃.
 34. The compound of claim 33 or apharmaceutically acceptable salt or solvate thereof, wherein A and B areeach —H.
 35. The compound of claim 33 or a pharmaceutically acceptablesalt or solvate thereof, wherein A is —H and B is —CH₃ or A is —CH₃ andB is —H.
 36. The compound of claim 32 or a pharmaceutically acceptablesalt or solvate thereof, wherein A and B together form a bridge suchthat the bridged-piperidine is:

wherein each R^(d) is independently —H, —(C₁-C₄)alkyl, -halo, or—C(halo)₃.
 37. The compound of claim 36 or a pharmaceutically acceptablesalt or solvate thereof, wherein A and B together form a bridge suchthat the bridged-piperidine is:


38. The compound of claim 37 or a pharmaceutically acceptable salt orsolvate thereof, wherein the A-B bridge of the bridged-piperidine is inthe endo-configuration with respect to the 5-membered,nitrogen-containing ring that is fused to the Q_(a) ring.
 39. Thecompound of claim 37 or a pharmaceutically acceptable salt or solvatethereof, wherein: (a) R¹ is —(C₃-C₁₄)cycloalkyl, —(C₅-C₁₄)cycloalkenyl,—(C₆-C₁₄)bicycloalkyl, —(C₇-C₁₄)bicycloalkenyl, or—(C₈-C₂₀)tricycloalkyl, each of which is unsubstituted or substitutedwith 1, 2, 3, or 4 independently selected R⁸ groups; and (b) each R⁸ isindependently —(C₁-C₄)alkyl, —(C₁-C₆)alkyl-C(═O)OR⁹,—N(R⁹)(C₁-C₆)alkyl-C(═O)OR⁹, —OR⁹, —C(halo)₃, —CH(halo)₂, —CH₂(halo),-halo, —N(R⁹)₂, —C(═O)N(T¹)(T²), or —C(═O)OR⁹.
 40. The compound of claim39 or a pharmaceutically acceptable salt or solvate thereof, wherein—Z—R¹ is:


41. The compound of claim 39 or a pharmaceutically acceptable salt orsolvate thereof, wherein —Z—R¹ is:

wherein each R^(z) is independently —H, —CH₃, or —CH₂CH₃.
 42. Thecompound of claim 41 or a pharmaceutically acceptable salt or solvatethereof, wherein —Z—R¹ is:

wherein R^(z) is —H, —CH₃, or —CH₂CH₃.
 43. The compound of claim 1 or apharmaceutically acceptable salt or solvate thereof, wherein a is 1 andR² is -halo.
 44. The compound of claim 1 or a pharmaceuticallyacceptable salt or solvate thereof, wherein the R¹ group is in theexo-configuration with respect to the A-B bridge of the bridgedpiperidine.
 45. A compound which is:

or a pharmaceutically acceptable salt thereof.
 46. The compound of claim45 which is:

or a pharmaceutically acceptable salt thereof.
 47. The compound of claim1, wherein the pharmaceutically acceptable salt is a hydrochloride-salt,a sodium-salt, a potassium-salt, or a para-toluenesulfonic acid-salt.48. The compound of claim 2, wherein the pharmaceutically acceptablesalt is a hydrochloride-salt, a sodium-salt, a potassium-salt, or apara-toluenesulfonic acid-salt.
 49. The compound of claim 3, wherein thepharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt,a potassium-salt, or a para-toluenesulfonic acid-salt.
 50. A compositioncomprising an effective amount of the compound or a pharmaceuticallyacceptable salt or solvate of the compound of claim 1 and apharmaceutically acceptable carrier or excipient.
 51. A compositioncomprising an effective amount of the compound or a pharmaceuticallyacceptable salt or solvate of the compound of claim 2 and apharmaceutically acceptable carrier or excipient.
 52. A compositioncomprising an effective amount of the compound or a pharmaceuticallyacceptable salt or solvate of the compound of claim 3 and apharmaceutically acceptable carrier or excipient.
 53. A method forpreparing a composition, comprising the step of admixing a compound or apharmaceutically acceptable salt or solvate of the compound of claim 1and a pharmaceutically acceptable carrier or excipient.
 54. A method formodulating ORL-1 receptor function in a cell, comprising contacting acell capable of expressing the ORL-1 receptor with an effective amountof the composition or the compound or a pharmaceutically acceptable saltor solvate of the compound of claim
 1. 55. The method of claim 54wherein the composition or the compound or the pharmaceuticallyacceptable salt or solvate of the compound acts as an agonist or as apartial agonist at the ORL-1 receptor.
 56. A method for treating pain inan animal, comprising administering to an animal in need thereof aneffective amount of the composition or the compound or apharmaceutically acceptable salt or solvate of the compound of claim 1.57. A method for treating a memory disorder, obesity, constipation,depression, dementia, Parkinsonism, anxiety, cough, diarrhea, high bloodpressure, epilepsy, anorexia/cachexia, urinary incontinence, or drugabuse in an animal, comprising administering to an animal in needthereof an effective amount of the composition or the compound or apharmaceutically acceptable salt or solvate of the compound of claim 1.